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Yakan A, Özkan H, Kaya U, Keçeli HH, Karaaslan I, Dalkiran S, Akçay A, Ünal N, Sariözkan S, Akyüz B, Arslan K, Çamdeviren B, Güngör G, Küçükoflaz M, Özbeyaz C. The effects of the feeding duration of propylene glycol on major meat quality parameters and substantial proteins in the muscle of Akkaraman lambs. Meat Sci 2024; 217:109615. [PMID: 39084122 DOI: 10.1016/j.meatsci.2024.109615] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Revised: 07/21/2024] [Accepted: 07/23/2024] [Indexed: 08/02/2024]
Abstract
In this study, the effects of propylene glycol (PG) on meat quality and molecular pathways related to energy metabolism in longissimus lumborum muscle on lambs were evaluated. Seventy-two lambs were divided into three groups consisting of 60th, 90th, and 120th of slaughter days. The dosage of the PG and slaughter days were the variables used in the study. Eight animals were slaughtered from each group on each day. The meat quality parameters (e.g., pH, protein, fatty acid profile) and IGF-1, IGFBP4, and DGAT1 (i.e., mRNA and protein levels) were evaluated. The pH 45 min post-slaughter was higher in PG groups on 120th day. On the 4th day after slaughter, the b value was the lowest in the PG3, while 7th day after slaughter it was highest in Con and PG3 on 90th day. The total n3 and n6 were lowest and the NV was highest on 120th day. The IGFBP4 was upregulated in the PG groups on all of the slaughter days. The DGAT1 was upregulated in the PG3 on the 90th day. The IGF-1, DGAT1, IGFBP4 protein levels were found to have increased in the PG3 on 90th day. The IGFBP4 was found to have decreased in the PG3 on 120th day. According to the results of the study, the oral administration of the PG at the 3 mL/kg live weight0.75 for at least 120 days may have positive effects on meat quality in lambs through the IGF-1, DGAT1, and IGFBP4 genes and the proteins encoded by these genes.
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Affiliation(s)
- Akın Yakan
- Hatay Mustafa Kemal University, Faculty of Veterinary Medicine, Department of Genetics, 31060, Hatay, Türkiye.
| | - Hüseyin Özkan
- Hatay Mustafa Kemal University, Faculty of Veterinary Medicine, Department of Genetics, 31060, Hatay, Türkiye
| | - Ufuk Kaya
- Hatay Mustafa Kemal University, Faculty of Veterinary Medicine, Department of Biostatistics, 31060, Hatay, Türkiye
| | - Hasan Hüseyin Keçeli
- Hatay Mustafa Kemal University, Faculty of Veterinary Medicine, Department of Genetics, 31060, Hatay, Türkiye
| | - Irem Karaaslan
- Hatay Mustafa Kemal University, Technology and Research & Development Center (MARGEM), 31060, Hatay, Türkiye
| | - Sevda Dalkiran
- Hatay Mustafa Kemal University, Institute of Health Sciences, Department of Molecular Biochemistry and Genetics, 31060, Hatay, Türkiye
| | - Aytaç Akçay
- Ankara University, Faculty of Veterinary Medicine, Department of Biostatistics, 06070 Ankara, Türkiye
| | - Necmettin Ünal
- Ankara University, Faculty of Veterinary Medicine, Department of Animal Science, 06070 Ankara, Türkiye
| | - Savaş Sariözkan
- Erciyes University, Faculty of Veterinary Medicine, Department of Animal Health Economics and Management, 38039 Kayseri, Türkiye
| | - Bilal Akyüz
- Erciyes University, Faculty of Veterinary Medicine, Department of Genetics, 38039 Kayseri, Türkiye
| | - Korhan Arslan
- Erciyes University, Faculty of Veterinary Medicine, Department of Genetics, 38039 Kayseri, Türkiye
| | - Baran Çamdeviren
- Hatay Mustafa Kemal University, Institute of Health Sciences, Department of Molecular Biochemistry and Genetics, 31060, Hatay, Türkiye
| | - Güven Güngör
- Bingöl University, Faculty of Veterinary Medicine, Department of Biostatistics, 12000 Bingöl, Türkiye
| | - Mehmet Küçükoflaz
- Kafkas University, Faculty of Veterinary Medicine, Department of Animal Health Economics and Management, 36300 Kars, Türkiye
| | - Ceyhan Özbeyaz
- Ankara University, Faculty of Veterinary Medicine, Department of Animal Science, 06070 Ankara, Türkiye
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2
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Notaro NM, Dyck DJ. Regulation of peripheral tissue substrate metabolism by the gut-derived hormone ghrelin. Metabol Open 2024; 21:100279. [PMID: 38487670 PMCID: PMC10937159 DOI: 10.1016/j.metop.2024.100279] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 02/21/2024] [Accepted: 02/22/2024] [Indexed: 03/17/2024] Open
Abstract
Ghrelin increases in the circulation prior to entrained mealtimes, with the acylated (AG) form functioning to stimulate food intake and growth hormone release. Acutely, AG induces whole-body insulin resistance, potentially to maintain glycemia between meals. Alternatively, chronic administration of both AG and the unacylated isoform of ghrelin (unAG) is associated with improved skeletal muscle insulin sensitivity as well as reduced intramuscular lipids and inflammation. This may be due to effects on lipid metabolism, with ghrelin promoting storage of fat in adipose and liver while stimulating oxidation in skeletal muscle, preventing ectopic lipid accumulation. This is of specific relevance in the handling of meal-derived lipids, as ghrelin rises preprandially with effects persisting for 2-3 h following exposure in skeletal muscle, coinciding with elevated plasma FFAs. We hypothesize that ghrelin acts as a preparatory signal for incoming lipids, as well as a regulatory hormone for their use and storage. The effects of ghrelin on skeletal muscle are lost with high fat diet feeding and physical inactivity, potentially being implicated in the pathogenesis of metabolic disease. This review summarizes the metabolic effects of both ghrelin isoforms on peripheral tissues including the pancreas, adipose, liver, and skeletal muscle. Additionally, we speculate on the physiological relevance of these effects in vivo and suggest that ghrelin may be a key regulatory hormone for nutrient handling in the postprandial state.
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Affiliation(s)
- Nicole M. Notaro
- Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, Canada
| | - David J. Dyck
- Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, Canada
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3
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Gajewska A, Strzelecki D, Gawlik-Kotelnicka O. Ghrelin as a Biomarker of "Immunometabolic Depression" and Its Connection with Dysbiosis. Nutrients 2023; 15:3960. [PMID: 37764744 PMCID: PMC10537261 DOI: 10.3390/nu15183960] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2023] [Revised: 09/08/2023] [Accepted: 09/10/2023] [Indexed: 09/29/2023] Open
Abstract
Ghrelin, a gastrointestinal peptide, is an endogenous ligand of growth hormone secretagogue receptor 1a (GHSR1a), which is mainly produced by X/A-like cells in the intestinal mucosa. Beyond its initial description as a growth hormone (GH) secretagogue stimulator of appetite, ghrelin has been revealed to have a wide range of physiological effects, for example, the modulation of inflammation; the improvement of cardiac performance; the modulation of stress, anxiety, taste sensation, and reward-seeking behavior; and the regulation of glucose metabolism and thermogenesis. Ghrelin secretion is altered in depressive disorders and metabolic syndrome, which frequently co-occur, but it is still unknown how these modifications relate to the physiopathology of these disorders. This review highlights the increasing amount of research establishing the close relationship between ghrelin, nutrition, microbiota, and disorders such as depression and metabolic syndrome, and it evaluates the ghrelinergic system as a potential target for the development of effective pharmacotherapies.
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Affiliation(s)
- Agata Gajewska
- Faculty of Medicine, Medical University of Lodz, 92-216 Lodz, Poland;
| | - Dominik Strzelecki
- Department of Affective and Psychotic Disorders, Medical University of Lodz, 92-216 Lodz, Poland;
| | - Oliwia Gawlik-Kotelnicka
- Department of Affective and Psychotic Disorders, Medical University of Lodz, 92-216 Lodz, Poland;
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4
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Iwakura H, Ensho T, Ueda Y. Desacyl-ghrelin, not just an inactive form of ghrelin?-A review of current knowledge on the biological actions of desacyl-ghrelin. Peptides 2023:171050. [PMID: 37392995 DOI: 10.1016/j.peptides.2023.171050] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 06/23/2023] [Accepted: 06/26/2023] [Indexed: 07/03/2023]
Abstract
Desacyl-ghrelin is a form of ghrelin which lacks acyl-modification of the third serine residue of ghrelin. Originally, desacyl-ghrelin was considered to be just an inactive form of ghrelin. More recently, however, it has been suggested to have various biological activities, including control of food intake, growth hormone, glucose metabolism, and gastric movement, and is involved in cell survival. In this review, we summarize the current knowledge of the biological actions of desacyl-ghrelin and the proposed mechanisms by which it exerts the effects.
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Affiliation(s)
- Hiroshi Iwakura
- Department of Pharmacotherapeutics, School of Pharmaceutical Science, Wakayama Medical University, 25-1 Shichibancho, Wakayama 640-8156, Japan.
| | - Takuya Ensho
- Department of Pharmacotherapeutics, School of Pharmaceutical Science, Wakayama Medical University, 25-1 Shichibancho, Wakayama 640-8156, Japan
| | - Yoko Ueda
- Department of Pharmacotherapeutics, School of Pharmaceutical Science, Wakayama Medical University, 25-1 Shichibancho, Wakayama 640-8156, Japan
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5
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Ma Y, Zhang H, Guo W, Yu L. Potential role of ghrelin in the regulation of inflammation. FASEB J 2022; 36:e22508. [PMID: 35983825 DOI: 10.1096/fj.202200634r] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 07/27/2022] [Accepted: 08/08/2022] [Indexed: 11/11/2022]
Abstract
Several diseases are caused or progress due to inflammation. In the past few years, accumulating evidence suggests that ghrelin, a gastric hormone of 28-amino acid residue length, exerts protective effects against inflammation by modulating the related pathways. This review focuses on ghrelin's anti-inflammatory and potential therapeutic effects in neurological, cardiovascular, respiratory, hepatic, gastrointestinal, and kidney disorders. Ghrelin significantly alleviates excessive inflammation and reduces damage to different target organs mainly by reducing the secretion of inflammatory cytokines, including interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α), and inhibiting the nuclear factor kappa-B (NF-κB) and NLRP3 inflammasome signaling pathways. Ghrelin also regulates inflammation and apoptosis through the p38 MAPK/c-Jun N-terminal kinase (JNK) signaling pathway; restores cerebral microvascular integrity, and attenuates vascular leakage. Ghrelin activates the phosphoInositide-3 kinase (PI3K)/protein kinase B (Akt) pathway and inhibits inflammatory responses in cardiovascular diseases and acute kidney injury. Some studies show that ghrelin exacerbates colonic and intestinal manifestations of colitis. Interestingly, some inflammatory states, such as non-alcoholic steatohepatitis, inflammatory bowel diseases, and chronic kidney disease, are often associated with high ghrelin levels. Thus, ghrelin may be a potential new therapeutic target for inflammation-related diseases.
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Affiliation(s)
- Yunxiao Ma
- Department of Endocrinology and Department of Interventional Therapy of First Hospital of Jilin University, State Key Laboratory for Zoonotic Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun, China
| | - Haifeng Zhang
- Department of Endocrinology and Department of Interventional Therapy of First Hospital of Jilin University, State Key Laboratory for Zoonotic Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun, China
| | - Weiying Guo
- Department of Endocrinology and Department of Interventional Therapy of First Hospital of Jilin University, State Key Laboratory for Zoonotic Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun, China
| | - Lu Yu
- Department of Endocrinology and Department of Interventional Therapy of First Hospital of Jilin University, State Key Laboratory for Zoonotic Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun, China
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6
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Kim HJ, Tak YJ, Lee SY, Seo JP. Effects of a 12-Week Diet versus Diet plus Aerobic and Resistance Exercise Program on Acylated and Desacylated Ghrelin, and Ghrelin O-Acyltransferase in Adolescent Girls with Obesity. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:1480. [PMID: 35162507 PMCID: PMC8835200 DOI: 10.3390/ijerph19031480] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/28/2021] [Revised: 01/14/2022] [Accepted: 01/26/2022] [Indexed: 11/28/2022]
Abstract
This study investigated the effects of a 12-week diet versus diet plus aerobic and resistance exercise programme on acylated ghrelin (AG), desacylated ghrelin (DAG), and ghrelin O-acyltransferase (GOAT) concentrations in girls with obesity. We randomised 30 adolescents with obesity to a 12-week aerobic and resistance exercise group (EG) or a control group (CG). At baseline and at 4, 8, and 12 weeks, we measured their body composition, lipid profile, glucose, AG, DAG, and GOAT concentrations. In the EG, the body fat percentage decreased by 2.37% and was significantly lower than that in the CG. The DAG concentrations significantly increased by 48.3% and 27.4% in the EG and CG, respectively. At 4, 8, and 12 weeks, DAG concentrations were significantly higher in the EG than in the CG. AG concentrations were higher at week 12 than at baseline in both groups. In both groups, the GOAT concentrations increased at weeks 8 and 12; however, no between-group differences were observed in the changes in GOAT concentrations. This study showed increased DAG concentrations and non-significant changes in AG and GOAT concentrations after a 12-week aerobic and resistance exercise programme in girls with obesity. These findings suggest that an aerobic and resistance exercise programme influences appetite-regulating hormones, mainly through changes in DAG concentrations.
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Affiliation(s)
- Hyun Jun Kim
- Department of Physical Education, Kyungnam University, Changwon 51767, Korea;
| | - Young Jin Tak
- Biomedical Research Institute, Pusan National University Hospital, Busan 49241, Korea;
- Department of Family Medicine, Pusan National University School of Medicine, Yangsan 50612, Korea
| | - Sang Yeoup Lee
- Family Medicine Clinic, Biomedical Research Institute, Pusan National University Yangsan Hospital, Yangsan 50612, Korea
- Department of Medical Education, Pusan National University School of Medicine, Yangsan 50612, Korea
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7
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Peris-Sampedro F, Le May MV, Stoltenborg I, Schéle E, Dickson SL. A skeleton in the cupboard in ghrelin research: Where are the skinny dwarfs? J Neuroendocrinol 2021; 33:e13025. [PMID: 34427011 DOI: 10.1111/jne.13025] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 07/09/2021] [Accepted: 08/05/2021] [Indexed: 12/15/2022]
Abstract
Based on studies delivering ghrelin or ghrelin receptor agonists, we have learned a great deal about the importance of the brain ghrelin signalling system for a wide range of physiological processes that include feeding behaviours, growth hormone secretion and glucose homeostasis. Because these processes can be considered as essential to life, the question arises as to why mouse models of depleted ghrelin signalling are not all skinny dwarfs with a host of behavioural and metabolic problems. Here, we provide a systematic detailed review of the phenotype of mice with deficient ghrelin signalling to help better understand the relevance and importance of the brain ghrelin signalling system, with a particular emphasis on those questions that remain unanswered.
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Affiliation(s)
- Fiona Peris-Sampedro
- Department of Physiology/Endocrine, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
| | - Marie V Le May
- Department of Physiology/Endocrine, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
| | - Iris Stoltenborg
- Department of Physiology/Endocrine, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
| | - Erik Schéle
- Department of Physiology/Endocrine, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
| | - Suzanne L Dickson
- Department of Physiology/Endocrine, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
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8
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Davis TR, Pierce MR, Novak SX, Hougland JL. Ghrelin octanoylation by ghrelin O-acyltransferase: protein acylation impacting metabolic and neuroendocrine signalling. Open Biol 2021; 11:210080. [PMID: 34315274 PMCID: PMC8316800 DOI: 10.1098/rsob.210080] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
The acylated peptide hormone ghrelin impacts a wide range of physiological processes but is most well known for controlling hunger and metabolic regulation. Ghrelin requires a unique posttranslational modification, serine octanoylation, to bind and activate signalling through its cognate GHS-R1a receptor. Ghrelin acylation is catalysed by ghrelin O-acyltransferase (GOAT), a member of the membrane-bound O-acyltransferase (MBOAT) enzyme family. The ghrelin/GOAT/GHS-R1a system is defined by multiple unique aspects within both protein biochemistry and endocrinology. Ghrelin serves as the only substrate for GOAT within the human proteome and, among the multiple hormones involved in energy homeostasis and metabolism such as insulin and leptin, acts as the only known hormone in circulation that directly stimulates appetite and hunger signalling. Advances in GOAT enzymology, structural modelling and inhibitor development have revolutionized our understanding of this enzyme and offered new tools for investigating ghrelin signalling at the molecular and organismal levels. In this review, we briefly summarize the current state of knowledge regarding ghrelin signalling and ghrelin/GOAT enzymology, discuss the GOAT structural model in the context of recently reported MBOAT enzyme superfamily member structures, and highlight the growing complement of GOAT inhibitors that offer options for both ghrelin signalling studies and therapeutic applications.
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Affiliation(s)
- Tasha R Davis
- Department of Chemistry, Syracuse University, Syracuse, NY 13244 USA
| | - Mariah R Pierce
- Department of Chemistry, Syracuse University, Syracuse, NY 13244 USA
| | - Sadie X Novak
- Department of Chemistry, Syracuse University, Syracuse, NY 13244 USA
| | - James L Hougland
- Department of Chemistry, Syracuse University, Syracuse, NY 13244 USA.,BioInspired Syracuse, Syracuse University, Syracuse, NY 13244 USA
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9
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Liang Y, Yin W, Yin Y, Zhang W. Ghrelin Based Therapy of Metabolic Diseases. Curr Med Chem 2021; 28:2565-2576. [PMID: 32538716 PMCID: PMC11213490 DOI: 10.2174/0929867327666200615152804] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 05/04/2020] [Accepted: 05/18/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND Ghrelin, a unique 28 amino acid peptide hormone secreted by the gastric X/A like cells, is an endogenous ligand of the growth hormone secretagogue receptor (GHSR). Ghrelin-GHSR signaling has been found to exert various physiological functions, including stimulation of appetite, regulation of body weight, lipid and glucose metabolism, and increase of gut motility and secretion. This system is thus critical for energy homeostasis. OBJECTIVE The objective of this review is to highlight the strategies of ghrelin-GHSR based intervention for therapy of obesity and its related metabolic diseases. RESULTS Therapeutic strategies of metabolic disorders targeting the ghrelin-GHSR pathway involve neutralization of circulating ghrelin by antibodies and RNA spiegelmers, antagonism of ghrelin receptor by its antagonists and inverse agonists, inhibition of ghrelin O-acyltransferase (GOAT), as well as potential pharmacological approach to decrease ghrelin synthesis and secretion. CONCLUSION Various compounds targeting the ghrelin-GHSR system have shown promising efficacy for the intervention of obesity and relevant metabolic disorders in animals and in vitro. Further clinical trials to validate their efficacy in human beings are urgently needed.
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Affiliation(s)
- Yuan Liang
- Key Laboratory of Molecular Cardiovascular Science, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Wenzhen Yin
- Key Laboratory of Molecular Cardiovascular Science, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Yue Yin
- Key Laboratory of Molecular Cardiovascular Science, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Weizhen Zhang
- Key Laboratory of Molecular Cardiovascular Science, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
- Department of Surgery, University of Michigan Medical Center, Ann Arbor, MI 48109-0346, USA
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10
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Kim S, Nam Y, Shin SJ, Park YH, Jeon SG, Kim JI, Kim MJ, Moon M. The Potential Roles of Ghrelin in Metabolic Syndrome and Secondary Symptoms of Alzheimer's Disease. Front Neurosci 2020; 14:583097. [PMID: 33071750 PMCID: PMC7543232 DOI: 10.3389/fnins.2020.583097] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Accepted: 08/26/2020] [Indexed: 12/12/2022] Open
Abstract
Although the major causative factors of Alzheimer's disease (AD) are the accumulation of amyloid β and hyperphosphorylated tau, AD can also be caused by metabolic dysfunction. The major clinical symptom of AD is cognitive dysfunction. However, AD is also accompanied by various secondary symptoms such as depression, sleep-wake disturbances, and abnormal eating behaviors. Interestingly, the orexigenic hormone ghrelin has been suggested to have beneficial effects on AD-related metabolic syndrome and secondary symptoms. Ghrelin improves lipid distribution and alters insulin sensitivity, effects that are hypothesized to delay the progression of AD. Furthermore, ghrelin can relieve depression by enhancing the secretion of hormones such as serotonin, noradrenaline, and orexin. Moreover, ghrelin can upregulate the expression of neurotrophic factors such as brain-derived neurotrophic factor and modulate the release of proinflammatory cytokines such as tumor necrosis factor α and interleukin 1β. Ghrelin alleviates sleep-wake disturbances by increasing the levels of melatonin, melanin-concentrating hormone. Ghrelin reduces the risk of abnormal eating behaviors by increasing neuropeptide Y and γ-aminobutyric acid. In addition, ghrelin increases food intake by inhibiting fatty acid biosynthesis. However, despite the numerous studies on the role of ghrelin in the AD-related pathology and metabolic disorders, there are only a few studies that investigate the effects of ghrelin on secondary symptoms associated with AD. In this mini review, our purpose is to provide the insights of future study by organizing the previous studies for the role of ghrelin in AD-related pathology and metabolic disorders.
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Affiliation(s)
- Sujin Kim
- Department of Biochemistry, College of Medicine, Konyang University, Daejeon, South Korea
| | - Yunkwon Nam
- Department of Biochemistry, College of Medicine, Konyang University, Daejeon, South Korea
| | - Soo Jung Shin
- Department of Biochemistry, College of Medicine, Konyang University, Daejeon, South Korea
| | - Yong Ho Park
- Department of Biochemistry, College of Medicine, Konyang University, Daejeon, South Korea
| | - Seong Gak Jeon
- Department of Biochemistry, College of Medicine, Konyang University, Daejeon, South Korea.,Department of Neural Development and Disease, Korea Brain Research Institute (KBRI), Daegu, South Korea
| | - Jin-Il Kim
- Department of Nursing, College of Nursing, Jeju National University, Jeju-si, South Korea
| | - Min-Jeong Kim
- Department of Biochemistry, College of Medicine, Konyang University, Daejeon, South Korea
| | - Minho Moon
- Department of Biochemistry, College of Medicine, Konyang University, Daejeon, South Korea
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11
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Au CC, Furness JB, Britt K, Oshchepkova S, Ladumor H, Soo KY, Callaghan B, Gerard C, Inghirami G, Mittal V, Wang Y, Huang XY, Spector JA, Andreopoulou E, Zumbo P, Betel D, Dow L, Brown KA. Three-dimensional growth of breast cancer cells potentiates the anti-tumor effects of unacylated ghrelin and AZP-531. eLife 2020; 9:56913. [PMID: 32667883 PMCID: PMC7363447 DOI: 10.7554/elife.56913] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Accepted: 06/25/2020] [Indexed: 12/31/2022] Open
Abstract
Breast cancer is the most common type of cancer in women and notwithstanding important therapeutic advances, remains the second leading cause of cancer-related death. Despite extensive research relating to the hormone ghrelin, responsible for the stimulation of growth hormone release and appetite, little is known of the effects of its unacylated form, especially in cancer. The present study aimed to characterize effects of unacylated ghrelin on breast cancer cells, define its mechanism of action, and explore the therapeutic potential of unacylated ghrelin or analog AZP-531. We report potent anti-tumor effects of unacylated ghrelin, dependent on cells being cultured in 3D in a biologically-relevant extracellular matrix. The mechanism of unacylated ghrelin-mediated growth inhibition involves activation of Gαi and suppression of MAPK signaling. AZP-531 also suppresses the growth of breast cancer cells in vitro and in xenografts, and may be a novel approach for the safe and effective treatment of breast cancer.
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Affiliation(s)
- CheukMan C Au
- Department of Medicine, Weill Cornell Medicine, New York, United States.,Centre for Cancer Research, Hudson Institute for Medical Research, Clayton, Australia.,Department of Molecular and Translational Sciences, Monash University, Clayton, Australia
| | - John B Furness
- Department of Anatomy and Neuroscience, University of Melbourne, Parkville, Australia
| | - Kara Britt
- Peter MacCallum Cancer Centre, Melbourne, Australia.,Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia
| | - Sofya Oshchepkova
- Department of Medicine, Weill Cornell Medicine, New York, United States
| | - Heta Ladumor
- Department of Medicine, Weill Cornell Medicine, New York, United States.,Weill Cornell Medicine - Qatar, Doha, Qatar
| | - Kai Ying Soo
- Centre for Cancer Research, Hudson Institute for Medical Research, Clayton, Australia
| | - Brid Callaghan
- Department of Anatomy and Neuroscience, University of Melbourne, Parkville, Australia
| | - Celine Gerard
- Centre for Cancer Research, Hudson Institute for Medical Research, Clayton, Australia
| | - Giorgio Inghirami
- Department of Pathology, Weill Cornell Medical College, New York, United States
| | - Vivek Mittal
- Department of Cardiothoracic Surgery, Department of Cell and Developmental Biology, Neuberger Berman Lung Cancer Center, Weill Cornell Medicine, New York, United States
| | - Yufeng Wang
- Department of Physiology and Biophysics, Weill Cornell Medical College of Cornell University, New York, United States
| | - Xin Yun Huang
- Department of Physiology and Biophysics, Weill Cornell Medical College of Cornell University, New York, United States
| | - Jason A Spector
- Department of Surgery, Weill Cornell Medicine, New York, United States
| | | | - Paul Zumbo
- Department of Physiology and Biophysics, Weill Cornell Medical College of Cornell University, New York, United States.,Applied Bioinformatics Core, Weill Cornell Medical College, New York, United States
| | - Doron Betel
- Department of Medicine, Weill Cornell Medicine, New York, United States.,Institute for Computational Biomedicine, Weill Cornell Medical College, New York, United States
| | - Lukas Dow
- Department of Medicine, Weill Cornell Medicine, New York, United States
| | - Kristy A Brown
- Department of Medicine, Weill Cornell Medicine, New York, United States.,Centre for Cancer Research, Hudson Institute for Medical Research, Clayton, Australia.,Department of Molecular and Translational Sciences, Monash University, Clayton, Australia
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Perna S, Spadaccini D, Gasparri C, Peroni G, Infantino V, Iannello G, Riva A, Petrangolini G, Alalwan TA, Al-Thawadi S, Rondanelli M. Association between des-acyl ghrelin at fasting and predictive index of muscle derangement, metabolic markers and eating disorders: a cross-sectional study in overweight and obese adults. Nutr Neurosci 2020; 25:336-342. [DOI: 10.1080/1028415x.2020.1752997] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Affiliation(s)
- Simone Perna
- Department of Biology, College of Science, University of Bahrain, Sakhir, Kingdom of Bahrain
| | - Daniele Spadaccini
- Endocrinology and Nutrition Unit, Azienda di Servizi alla Persona ‘Istituto Santa Margherita’, University of Pavia, Pavia, Italy
| | - Clara Gasparri
- Endocrinology and Nutrition Unit, Azienda di Servizi alla Persona ‘Istituto Santa Margherita’, University of Pavia, Pavia, Italy
| | - Gabriella Peroni
- Endocrinology and Nutrition Unit, Azienda di Servizi alla Persona ‘Istituto Santa Margherita’, University of Pavia, Pavia, Italy
| | - Vittoria Infantino
- Department of Public Health, Experimental and Forensic Medicine, Unit of Human and Clinical Nutrition, University of Pavia, Pavia, Italy
| | - Giancarlo Iannello
- General Management, Azienda di Servizi alla Persona ‘Istituto Santa Margherita’, Pavia, Italy
| | - Antonella Riva
- Research and Development Department, Indena SpA, Milan, Italy
| | | | - Tariq A. Alalwan
- Department of Biology, College of Science, University of Bahrain, Sakhir, Kingdom of Bahrain
| | - Salwa Al-Thawadi
- Department of Biology, College of Science, University of Bahrain, Sakhir, Kingdom of Bahrain
| | - Mariangela Rondanelli
- Department of Public Health, Experimental and Forensic Medicine, Unit of Human and Clinical Nutrition, University of Pavia, Pavia, Italy
- IRCCS Mondino Foundation, Pavia, Italy
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13
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Raghay K, Akki R, Bensaid D, Errami M. Ghrelin as an anti-inflammatory and protective agent in ischemia/reperfusion injury. Peptides 2020; 124:170226. [PMID: 31786283 DOI: 10.1016/j.peptides.2019.170226] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Revised: 11/27/2019] [Accepted: 11/27/2019] [Indexed: 02/06/2023]
Abstract
Ischemia/reperfusion (I/R) continue to be the most frequent cause of damaged tissues. Injured tissues resulted from the first ischemic insult, which is determined by the interruption in the blood supply, followed by subsequent impairment induced by reperfusion. In addition, ischemia-reperfusion injury is mediated by tumor necrosis factor (TNF) and other cytokines that activate complements and proteases responsible for free radical production. However, earlier studies have reported the protective roles of bioactive peptides during ischemia reperfusion injury. In fact, ghrelin is a peptide hormone discovered since 1999 as GH secretagogue and its production was identified in gastric X/A-like endocrine cells in rats and P/D1 type cells in humans. To date, this peptide receives growing attention due to its pleiotropic action in the organism and its role in maintaining energy homeostasis. Ghrelin is also involved in stress responses, assuming a modulatory action on immune pathways. Previous studies have identified many other functions related to an anti-inflammatory role in ischemia reperfusion injury. Under these challenging conditions, studies described acylated and unacylated ghrelin in activation and/or inhibition processes related to ischemia-reperfusion injury. The aim of this article is to provide a minireview about ghrelin mechanisms involved in the proinflammatory response of I/R injury. However, the regulatory processes of ghrelin in this pathologic event are still very limited and warrant further investigation.
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Affiliation(s)
- K Raghay
- Department of Biology, Faculty of Sciences, Abdelmalek Essaadi University, Tetouan, Morocco.
| | - R Akki
- Department of Biology, Faculty of Sciences, Abdelmalek Essaadi University, Tetouan, Morocco.
| | - D Bensaid
- Department of Biology, Faculty of Sciences, Abdelmalek Essaadi University, Tetouan, Morocco.
| | - M Errami
- Department of Biology, Faculty of Sciences, Abdelmalek Essaadi University, Tetouan, Morocco.
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14
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Akalu Y, Molla MD, Dessie G, Ayelign B. Physiological Effect of Ghrelin on Body Systems. Int J Endocrinol 2020; 2020:1385138. [PMID: 32565790 PMCID: PMC7267865 DOI: 10.1155/2020/1385138] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Revised: 02/08/2020] [Accepted: 05/13/2020] [Indexed: 02/06/2023] Open
Abstract
Ghrelin is a relatively novel multifaceted hormone that has been found to exert a plethora of physiological effects. In this review, we found/confirmed that ghrelin has effect on all body systems. It induces appetite; promotes the use of carbohydrates as a source of fuel while sparing fat; inhibits lipid oxidation and promotes lipogenesis; stimulates the gastric acid secretion and motility; improves cardiac performance; decreases blood pressure; and protects the kidneys, heart, and brain. Ghrelin is important for learning, memory, cognition, reward, sleep, taste sensation, olfaction, and sniffing. It has sympatholytic, analgesic, antimicrobial, antifibrotic, and osteogenic effects. Moreover, ghrelin makes the skeletal muscle more excitable and stimulates its regeneration following injury; delays puberty; promotes fetal lung development; decreases thyroid hormone and testosterone; stimulates release of growth hormone, prolactin, glucagon, adrenocorticotropic hormone, cortisol, vasopressin, and oxytocin; inhibits insulin release; and promotes wound healing. Ghrelin protects the body by different mechanisms including inhibition of unwanted inflammation and induction of autophagy. Having a clear understanding of the ghrelin effect in each system has therapeutic implications. Future studies are necessary to elucidate the molecular mechanisms of ghrelin actions as well as its application as a GHSR agonist to treat most common diseases in each system without any paradoxical outcomes on the other systems.
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Affiliation(s)
- Yonas Akalu
- Department of Physiology, School of Medicine, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Meseret Derbew Molla
- Department of Biochemistry, School of Medicine, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Gashaw Dessie
- Department of Biochemistry, School of Medicine, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Birhanu Ayelign
- Department of Immunology and Molecular Biology, School of Biomedical and Laboratory Science, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
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15
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Gortan Cappellari G, Barazzoni R. Ghrelin forms in the modulation of energy balance and metabolism. Eat Weight Disord 2019; 24:997-1013. [PMID: 30353455 DOI: 10.1007/s40519-018-0599-6] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Accepted: 10/16/2018] [Indexed: 02/06/2023] Open
Abstract
Ghrelin is a gastric hormone circulating in acylated (AG) and unacylated (UnAG) forms. This narrative review aims at presenting current emerging knowledge on the impact of ghrelin forms on energy balance and metabolism. AG represents ~ 10% of total plasma ghrelin, has an appetite-stimulating effect and is the only form for which a receptor has been identified. Moreover, other metabolic AG-induced effects have been reported, including the modulation of glucose homeostasis with stimulation of liver gluconeogenesis, the increase of fat mass and the improvement of skeletal muscle mitochondrial function. On the other hand, UnAG has no orexigenic effects, however recent reports have shown that it is directly involved in the modulation of skeletal muscle energy metabolism by improving a cluster of interlinked functions including mitochondrial redox activities, tissue inflammation and insulin signalling and action. These findings are in agreement with human studies which show that UnAG circulating levels are positively associated with insulin sensitivity both in metabolic syndrome patients and in a large cohort from the general population. Moreover, ghrelin acylation is regulated by a nutrient sensor mechanism, specifically set on fatty acids availability. These recent findings consistently point towards a novel independent role of UnAG as a regulator of muscle metabolic pathways maintaining energy status and tissue anabolism. While a specific receptor for UnAG still needs to be identified, recent evidence strongly supports the hypothesis that the modulation of ghrelin-related molecular pathways, including those involved in its acylation, may be a potential novel target in the treatment of metabolic derangements in disease states characterized by metabolic and nutritional complications.Level of evidence Level V, narrative review.
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Affiliation(s)
- Gianluca Gortan Cappellari
- Department of Medical, Surgical and Health Sciences, University of Trieste, Strada di Fiume, 447, 34149, Trieste, Italy.
| | - Rocco Barazzoni
- Department of Medical, Surgical and Health Sciences, University of Trieste, Strada di Fiume, 447, 34149, Trieste, Italy.
- Azienda Sanitaria Universitaria Integrata di Trieste (ASUITS), Trieste, Italy.
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16
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Tauber M, Coupaye M, Diene G, Molinas C, Valette M, Beauloye V. Prader-Willi syndrome: A model for understanding the ghrelin system. J Neuroendocrinol 2019; 31:e12728. [PMID: 31046160 DOI: 10.1111/jne.12728] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Revised: 04/26/2019] [Accepted: 04/29/2019] [Indexed: 02/07/2023]
Abstract
Subsequent to the discovery of ghrelin as the endogenous ligand of growth hormone secretagogue receptor 1a, this unique gut peptide has been found to exert numerous physiological effects, such as appetite stimulation and lipid accumulation via the central regulating mechanisms in the hypothalamus, stimulation of gastric motility, regulation of glucose metabolism and brown fat thermogenesis, and modulation of stress, anxiety, taste sensation, reward-seeking behaviour and the sleep/wake cycle. Prader-Willi syndrome (PWS) has been described as a unique pathological state characterised by severe obesity and high circulating levels of ghrelin. It was hypothesised that hyperghrelinaemia would explain at least a part of the feeding behaviour and body composition of PWS patients, who are characterised by hyperphagia, an obsession with food and food-seeking, and increased adiposity. Initially, the link between hyperghrelinaemia and growth hormone deficiency, which is observed in 90% of the children with PWS, was not fully understood. Over the years, however, the increasing knowledge on ghrelin, PWS features and the natural history of the disease has led to a more comprehensive description of the abnormal ghrelin system and its role in the pathophysiology of this rare and complex neurodevelopmental genetic disease. In the present study, we (a) present the current view of PWS; (b) explain its natural history, including recent data on the ghrelin system in PWS patients; and (c) discuss the therapeutic approach of modulating the ghrelin system in these patients and the first promising results.
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Affiliation(s)
- Maithé Tauber
- Centre de Référence du Syndrome de Prader-Willi, Hôpital des Enfants, CHU Toulouse, Toulouse, France
- Axe Pédiatrique du CIC 9302/INSERM. Hôpital des Enfants, Toulouse, France
- INSERM U1043, Centre de Physiopathologie de Toulouse Purpan, Université Paul Sabatier, Toulouse, France
| | - Muriel Coupaye
- Service de Nutrition, Centre de Référence du Syndrome de Prader-Willi Assistance-Publique Hôpitaux de Paris (AP-HP), CHU Pitié-Salpêtrière, Sorbonne Université, Paris, France
| | - Gwenaelle Diene
- Centre de Référence du Syndrome de Prader-Willi, Hôpital des Enfants, CHU Toulouse, Toulouse, France
- INSERM, UMR 1027- Université Toulouse III Hôpital Paule de Viguier, Toulouse, France
| | - Catherine Molinas
- Centre de Référence du Syndrome de Prader-Willi, Hôpital des Enfants, CHU Toulouse, Toulouse, France
- Axe Pédiatrique du CIC 9302/INSERM. Hôpital des Enfants, Toulouse, France
- INSERM U1043, Centre de Physiopathologie de Toulouse Purpan, Université Paul Sabatier, Toulouse, France
| | - Marion Valette
- Centre de Référence du Syndrome de Prader-Willi, Hôpital des Enfants, CHU Toulouse, Toulouse, France
- Axe Pédiatrique du CIC 9302/INSERM. Hôpital des Enfants, Toulouse, France
| | - Veronique Beauloye
- Unité d'Endocrinologie Pédiatrique, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium
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Gray SM, Page LC, Tong J. Ghrelin regulation of glucose metabolism. J Neuroendocrinol 2019; 31:e12705. [PMID: 30849212 PMCID: PMC6688917 DOI: 10.1111/jne.12705] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Revised: 03/04/2019] [Accepted: 03/05/2019] [Indexed: 12/14/2022]
Abstract
Ghrelin and its receptor, the growth hormone secretagogue receptor 1a (GHSR1a), are implicated in the regulation of glucose metabolism via direct actions in the pancreatic islet, as well as peripheral insulin-sensitive tissues and the brain. Although many studies have explored the role of ghrelin in glucose tolerance and insulin secretion, a complete mechanistic understanding remains to be clarified. This review highlights the local expression and function of ghrelin and GHSR1a in pancreatic islets and how this axis may modulate insulin secretion from pancreatic β-cells. Additionally, we discuss the effect of ghrelin on in vivo glucose metabolism in rodents and humans, as well as the metabolic circumstances under which the action of ghrelin may predominate.
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Affiliation(s)
- Sarah. M. Gray
- Duke Molecular Physiology Institute, Duke University, Durham, NC 27701
| | - Laura C. Page
- Division of Endocrinology, Department of Pediatrics, Duke University, Durham, NC 27701
| | - Jenny Tong
- Duke Molecular Physiology Institute, Duke University, Durham, NC 27701
- Division of Endocrinology, Department of Pediatrics, Duke University, Durham, NC 27701
- Division of Endocrinology, Metabolism, and Nutrition, Department of Medicine, Duke University, Durham, NC 27701
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18
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Mani BK, Shankar K, Zigman JM. Ghrelin's Relationship to Blood Glucose. Endocrinology 2019; 160:1247-1261. [PMID: 30874792 PMCID: PMC6482034 DOI: 10.1210/en.2019-00074] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Accepted: 03/09/2019] [Indexed: 12/16/2022]
Abstract
Much effort has been directed at studying the orexigenic actions of administered ghrelin and the potential effects of the endogenous ghrelin system on food intake, food reward, body weight, adiposity, and energy expenditure. Although endogenous ghrelin's actions on some of these processes remain ambiguous, its glucoregulatory actions have emerged as well-recognized features during extreme metabolic conditions. The blood glucose-raising actions of ghrelin are beneficial during starvation-like conditions, defending against life-threatening falls in blood glucose, but they are seemingly detrimental in obese states and in certain monogenic forms of diabetes, contributing to hyperglycemia. Also of interest, blood glucose negatively regulates ghrelin secretion. This article reviews the literature suggesting the existence of a blood glucose-ghrelin axis and highlights the factors that mediate the glucoregulatory actions of ghrelin, especially during metabolic extremes such as starvation and diabetes.
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Affiliation(s)
- Bharath K Mani
- Division of Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
- Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
- Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Kripa Shankar
- Division of Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
- Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
- Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Jeffrey M Zigman
- Division of Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
- Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
- Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas
- Correspondence: Jeffrey M. Zigman, MD, PhD, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390. E-mail:
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Patro-Małysza J, Trojnar M, Kimber-Trojnar Ż, Mierzyński R, Bartosiewicz J, Oleszczuk J, Leszczyńska-Gorzelak B. FABP4 in Gestational Diabetes-Association between Mothers and Offspring. J Clin Med 2019; 8:jcm8030285. [PMID: 30818771 PMCID: PMC6462903 DOI: 10.3390/jcm8030285] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2018] [Revised: 02/18/2019] [Accepted: 02/22/2019] [Indexed: 12/16/2022] Open
Abstract
Fetuses exposed to gestational diabetes mellitus (GDM) have a higher risk of abnormal glucose homeostasis in later life. The molecular mechanisms of this phenomenon are still not fully understood. Fatty acid binding protein 4 (FABP4) appears to be one of the most probable candidates involved in the pathophysiology of GDM. The main aim of the study was to investigate whether umbilical cord serum FABP4 concentrations are altered in term neonates born to GDM mothers. Two groups of subjects were selected—28 healthy controls and 26 patients with GDM. FABP4, leptin, and ghrelin concentrations in the umbilical cord serum, maternal serum, and maternal urine were determined via an enzyme-linked immunosorbent assay. The umbilical cord serum FABP4 levels were higher in the GDM offspring and were directly associated with the maternal serum FABP4 and leptin levels, as well as the prepregnancy body mass index (BMI) and the BMI at and after delivery; however, they correlated negatively with birth weight and lipid parameters. In the multiple linear regression models, the umbilical cord serum FABP4 concentrations depended positively on the maternal serum FABP4 and negatively on the umbilical cord serum ghrelin levels and the high-density lipoprotein cholesterol. There are many maternal variables that can affect the level of FABP4 in the umbilical cord serum, thus, their evaluation requires further investigation.
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Affiliation(s)
- Jolanta Patro-Małysza
- Department of Obstetrics and Perinatology, Medical University of Lublin, 20-090 Lublin, Poland.
| | - Marcin Trojnar
- Department of Internal Medicine, Medical University of Lublin, 20-081 Lublin, Poland.
| | - Żaneta Kimber-Trojnar
- Department of Obstetrics and Perinatology, Medical University of Lublin, 20-090 Lublin, Poland.
| | - Radzisław Mierzyński
- Department of Obstetrics and Perinatology, Medical University of Lublin, 20-090 Lublin, Poland.
| | - Jacek Bartosiewicz
- Department of Obstetrics and Perinatology, Medical University of Lublin, 20-090 Lublin, Poland.
| | - Jan Oleszczuk
- Department of Obstetrics and Perinatology, Medical University of Lublin, 20-090 Lublin, Poland.
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20
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Yang EI, Lee CH, Che DN, Jang SI, Kim YS. Biological activities of water-soluble polysaccharides from Opuntia humifusa stem in high-fat-diet-fed mice. J Food Biochem 2019; 43:e12806. [PMID: 31353577 DOI: 10.1111/jfbc.12806] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2018] [Revised: 12/10/2018] [Accepted: 01/29/2019] [Indexed: 11/28/2022]
Abstract
Water-soluble polysaccharide (WSP) of Opuntia humifusa stems was extracted and its biological activities in mice fed with a high-fat diet (HFD) were investigated. The mice were treated with oral doses of WSP for 4 weeks. Body weight, fat mass, serum lipid, and hormone profiles, gastrointestinal tract changes were evaluated. WSP treatment resulted in a decrease in fat mass and improvement of lipid and hormone profiles associated with HFD consumption. In addition, WSP improved the gastrointestinal health of the mice by increasing ghrelin-releasing cells and serotonin-positive cells and boosted immune functions by increasing the expression of CD4+ cells and nitric oxide synthase. Also, WSP treatment reduced gastrointestinal transit time and increased fecal moisture content. These findings suggest that a sufficient intake of WSP from O. humifusa can be beneficial in preventing disorders that are associated with the consumption of HFD including the preservation of gastrointestinal health. PRACTICAL APPLICATIONS: Opuntia humifusa is a traditional edible plant widely eaten in Asia for its high concentrations of vitamin C, polyphenols, and flavonoids. The research investigated the biological activity of WSP extracted from O. humifusa stems. The data obtained from this study sheds light on the use of plant-based polysaccharides in nutraceutical industries as potential functional food materials for the prevention of HFD-related disorders and improvement of gastrointestinal health. The results of this research could serve as a base for further research on this polysaccharide as a source of functional polysaccharides and promotes its usage on a large scale in functional food materials.
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Affiliation(s)
- Eun-In Yang
- Research Center for Industrial Development of Biofood Materials, Chonbuk National University, Jeonju, Republic of Korea
| | - Chang-Hyun Lee
- Department of Anatomy, College of Oriental Medicine, Woosuk University, Wanju, Republic of Korea
| | - Denis Nchang Che
- Department of Food Science and Technology, Chonbuk National University, Jeonju, Republic of Korea
| | - Seon-Il Jang
- Department of Health Management, Jeonju University, Jeonju, Republic of Korea
| | - Young-Soo Kim
- Research Center for Industrial Development of Biofood Materials, Chonbuk National University, Jeonju, Republic of Korea.,Department of Food Science and Technology, Chonbuk National University, Jeonju, Republic of Korea
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Kimber-Trojnar Ż, Patro-Małysza J, Trojnar M, Skórzyńska-Dziduszko KE, Bartosiewicz J, Oleszczuk J, Leszczyńska-Gorzelak B. Fatty Acid-Binding Protein 4-An "Inauspicious" Adipokine-In Serum and Urine of Post-Partum Women with Excessive Gestational Weight Gain and Gestational Diabetes Mellitus. J Clin Med 2018; 7:jcm7120505. [PMID: 30513800 PMCID: PMC6306707 DOI: 10.3390/jcm7120505] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Revised: 11/25/2018] [Accepted: 11/30/2018] [Indexed: 12/17/2022] Open
Abstract
The exact roles of adipokines in the pathogenesis of type 2 diabetes and obesity are still unclear. The aim of the study was to evaluate fatty acid binding protein 4 (FABP4) concentrations in the serum and urine of women with excessive gestational weight gain (EGWG) and gestational diabetes mellitus (GDM) in the early post-partum period, with reference to their laboratory test results, body composition, and hydration status. The study subjects were divided into three groups: 24 healthy controls, 24 mothers with EGWG, and 22 GDM patients. Maternal body composition and hydration status were evaluated by the bioelectrical impedance analysis (BIA) method. Concentrations of FABP4, leptin, and ghrelin were determined via enzyme-linked immunosorbent assay (ELISA). Healthy women were characterized by the lowest serum leptin concentrations and by a negative correlation between the serum and urine FABP4 levels. Serum FABP4 levels were the highest in the GDM group. Serum FABP4 and leptin concentrations correlated positively in the GDM group. The EGWG group had the highest degree of BIA disturbances in the early puerperium and positive correlations between the urine FABP4 and serum leptin and ghrelin concentrations. The physiological and pathological significance of these findings requires further elucidation.
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Affiliation(s)
- Żaneta Kimber-Trojnar
- Chair and Department of Obstetrics and Perinatology, Medical University of Lublin, 20-090 Lublin, Poland.
| | - Jolanta Patro-Małysza
- Chair and Department of Obstetrics and Perinatology, Medical University of Lublin, 20-090 Lublin, Poland.
| | - Marcin Trojnar
- Chair and Department of Internal Medicine, Medical University of Lublin, 20-081 Lublin, Poland.
| | | | - Jacek Bartosiewicz
- Chair and Department of Obstetrics and Perinatology, Medical University of Lublin, 20-090 Lublin, Poland.
| | - Jan Oleszczuk
- Chair and Department of Obstetrics and Perinatology, Medical University of Lublin, 20-090 Lublin, Poland.
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Dallak M. Unacylated ghrelin stimulates steroidogenesis in lean rats and reverses reproductive dysfunction in high fat diet-fed rats. Syst Biol Reprod Med 2018; 65:129-146. [DOI: 10.1080/19396368.2018.1523971] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Affiliation(s)
- Mohammad Dallak
- Department of Physiology, College of Medicine, King Khalid University, Abha, Saudi Arabia
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23
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Al-Massadi O, Müller T, Tschöp M, Diéguez C, Nogueiras R. Ghrelin and LEAP-2: Rivals in Energy Metabolism. Trends Pharmacol Sci 2018; 39:685-694. [DOI: 10.1016/j.tips.2018.06.004] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2018] [Revised: 06/04/2018] [Accepted: 06/04/2018] [Indexed: 01/13/2023]
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Dallak MA. Acylated ghrelin induces but deacylated ghrelin prevents hepatic steatosis and insulin resistance in lean rats: Effects on DAG/ PKC/JNK pathway. Biomed Pharmacother 2018; 105:299-311. [PMID: 29860222 DOI: 10.1016/j.biopha.2018.05.098] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Revised: 05/20/2018] [Accepted: 05/21/2018] [Indexed: 12/19/2022] Open
Abstract
This study investigated the molecular effects of acylated (AG) and unacylated ghrelin (UAG) or their combination on hepatic lipogenesis pathways and DAG/PKC/JNK signaling in the livers of lean rats fed standard diet. Male rats (n = 10) were classified as control + vehicle (saline, 200 μl), AG, UAG, and AG + UAG-treated groups. All treatments were given at final doses of 200 ng/kg of for 14 days (twice/day, S.C). Administration of AG significantly enhanced circulatory levels of AG and UAG turning the normal ratio of AG/UAG from 1:2.5 to 1:1.2. However, while UAG didn't affect circulatory levels of AG, administration of UAG alone or in combination with AG resulted in AG/UAG ratios of 1:7 and 1:3, respectively. Independent of food intake nor the development of peripheral IR, AG increased hepatic DAG, TGs and CHOL contents and induced hepatic IR. Mechanism of action include 1) upregulation of mRNA and protein levels of DGAT-2 and mtGPAT-1, SREBP-1 and SCD-1, and 2) inhibition of fatty acids (FAs) oxidation mediated by inhibition of AMPK/ PPAR-α/CPT-1 axis. Consequently, AG induced membranous translocation of PKCδ and PKCε leading to activation of JNK and significant inhibition of insulin signaling under basal and insulin stimulation as evident by decreases in the phosphorylation levels of IRS (Tyr612) and Akt (Thr318) and increased phosphorylation of IRS (Ser307). However, while UAG only activated FAs oxidation in control rats, it reversed all alterations in all measured biochemical endpoints seen in the AG-treated group, when administered in combination with AG, leading to significant decreases in hepatic fat accumulation and prevention of hepatic IR. In conclusion, while exogenous administration of AG is at high risk of developing steatohepatitis and hepatic IR, co-administration of a balanced dose of UAG reduces this risk and inhibits hepatic lipid accumulation and enhance hepatic insulin signaling.
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Affiliation(s)
- Mohammad A Dallak
- Department of Physiology, College of Medicine, King's Khalid University, Abha, 61241, Saudi Arabia.
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Green BD, Grieve DJ. Biochemical properties and biological actions of obestatin and its relevence in type 2 diabetes. Peptides 2018; 100:249-259. [PMID: 29412827 DOI: 10.1016/j.peptides.2017.12.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2017] [Revised: 12/05/2017] [Accepted: 12/06/2017] [Indexed: 12/15/2022]
Abstract
Obestatin was initially discovered in rat stomach extract, and although it is principally produced in the gastric mucosa, it can be found throughout the gastrointestinal tract. This 23-amino acid C-terminally amidated peptide is derived from preproghrelin and has been ascribed a wide range of metabolic effects relevant to type 2 diabetes. Obestatin reportedly inhibits gastrointestinal motility, reduces food intake and lowers body weight and improves lipid metabolism. Furthermore, it appears to exert actions on the pancreatic β-cell, most notably increasing β-cell mass and upregulating genes associated with insulin production and β-cell regeneration, with relevance to type 2 diabetes. It is becoming evident that obestatin also exerts pleiotropic effects on the cardiovascular system, possibly modulating blood pressure, endothelial function and triggering cardioprotective mechanisms, which may be important in determining cardiovascular outcomes in type 2 diabetes. Furthermore, it seems that like other gut peptides obestatin has neuroprotective properties. This review examines the biochemical properties of the obestatin peptide (its structure, sequence, stability and distribution) and the candidate receptors through which it may act. It provides a balanced examination of the reported pancreatic and extrapancreatic actions of obestatin and evaluates its potential relevance with respect to diabetes therapy, together with discussion of direct evidence linking alterations in obestatin signalling with obesity/diabetes and other diseases.
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Affiliation(s)
- Brian D Green
- Institute for Global Food Security, School of Biological Sciences, Queen's University Belfast, Belfast, BT9 5BN, UK.
| | - David J Grieve
- Centre for Experimental Medicine, Queen's University Belfast, Belfast, BT9 7AE, UK
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Poher AL, Tschöp MH, Müller TD. Ghrelin regulation of glucose metabolism. Peptides 2018; 100:236-242. [PMID: 29412824 PMCID: PMC5805851 DOI: 10.1016/j.peptides.2017.12.015] [Citation(s) in RCA: 99] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2017] [Revised: 12/15/2017] [Accepted: 12/16/2017] [Indexed: 02/07/2023]
Abstract
The a 28-amino acid peptide ghrelin was discovered in 1999 as a growth hormone (GH) releasing peptide. Soon after its discovery, ghrelin was found to increase body weight and adiposity by acting on the hypothalamic melanocortinergic system. Subsequently, ghrelin was found to exert a series of metabolic effects, overall testifying ghrelin a pleiotropic nature of broad pharmacological interest. Ghrelin acts through the growth hormone secretagogue-receptor (GHS-R), a seven transmembrane G protein-coupled receptor with high expression in the anterior pituitary, pancreatic islets, thyroid gland, heart and various regions of the brain. Among ghrelins numerous metabolic effects are the most prominent the stimulation of appetite via activation of orexigenic hypothalamic neurocircuits and the food-intake independent stimulation of lipogenesis, which both together lead to an increase in body weight and adiposity. Ghrelin effects beyond the regulation of appetite and GH secretion include the regulation of gut motility, sleep-wake rhythm, taste sensation, reward seeking behaviour, and the regulation of glucose metabolism. The latter received recently increasing recognition because pharmacological inhibition of ghrelin signaling might be of therapeutic value to improve insuin resistance and type 2 diabetes. In this review we highlight the multifaceted nature of ghrelin and summarize its glucoregulatory action and discuss the pharmacological value of ghrelin pathway inhibition for the treatment of glucose intolerance and type 2 diabetes.
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Affiliation(s)
- Anne-Laure Poher
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center (HDC), Helmholtz Zentrum München and German National Diabetes Center (DZD), 85764, Neuherberg, Germany
| | - Matthias H Tschöp
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center (HDC), Helmholtz Zentrum München and German National Diabetes Center (DZD), 85764, Neuherberg, Germany; Division of Metabolic Diseases, Department of Medicine, Technische Universität München, 80333, Munich, Germany
| | - Timo D Müller
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center (HDC), Helmholtz Zentrum München and German National Diabetes Center (DZD), 85764, Neuherberg, Germany.
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Ugwu FN, Yu AP, Sin TK, Tam BT, Lai CW, Wong SC, Siu PM. Protective Effect of Unacylated Ghrelin on Compression-Induced Skeletal Muscle Injury Mediated by SIRT1-Signaling. Front Physiol 2017; 8:962. [PMID: 29225581 PMCID: PMC5705540 DOI: 10.3389/fphys.2017.00962] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2017] [Accepted: 11/10/2017] [Indexed: 12/30/2022] Open
Abstract
Unacylated ghrelin, the predominant form of circulating ghrelin, protects myotubes from cell death, which is a known attribute of pressure ulcers. In this study, we investigated whether unacylated ghrelin protects skeletal muscle from pressure-induced deep tissue injury by abolishing necroptosis and apoptosis signaling and whether these effects were mediated by SIRT1 pathway. Fifteen adult Sprague Dawley rats were assigned to receive saline or unacylated ghrelin with or without EX527 (a SIRT1 inhibitor). Animals underwent two 6-h compression cycles with 100 mmHg static pressure applied over the mid-tibialis region of the right limb whereas the left uncompressed limb served as the intra-animal control. Muscle tissues underneath the compression region, and at the similar region of the opposite uncompressed limb, were collected for analysis. Unacylated ghrelin attenuated the compression-induced muscle pathohistological alterations including rounding contour of myofibers, extensive nucleus accumulation in the interstitial space, and increased interstitial space. Unacylated ghrelin abolished the increase in necroptosis proteins including RIP1 and RIP3 and attenuated the elevation of apoptotic proteins including p53, Bax, and AIF in the compressed muscle. Furthermore, unacylated ghrelin opposed the compression-induced phosphorylation and acetylation of p65 subunit of NF-kB. The anti-apoptotic effect of unacylated ghrelin was shown by a decrease in apoptotic DNA fragmentation and terminal dUTP nick-end labeling index in the compressed muscle. The protective effects of unacylated ghrelin vanished when co-treated with EX527. Our findings demonstrated that unacylated ghrelin protected skeletal muscle from compression-induced injury. The myoprotective effects of unacylated ghrelin on pressure-induced tissue injury were associated with SIRT1 signaling.
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Affiliation(s)
- Felix N Ugwu
- Department of Health Technology and Informatics, Faculty of Health and Social Sciences, Hong Kong Polytechnic University, Kowloon, Hong Kong
| | - Angus P Yu
- School of Public Health, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, Hong Kong
| | - Thomas K Sin
- Department of Health Technology and Informatics, Faculty of Health and Social Sciences, Hong Kong Polytechnic University, Kowloon, Hong Kong
| | - Bjorn T Tam
- Department of Health Technology and Informatics, Faculty of Health and Social Sciences, Hong Kong Polytechnic University, Kowloon, Hong Kong
| | - Christopher W Lai
- Department of Health Technology and Informatics, Faculty of Health and Social Sciences, Hong Kong Polytechnic University, Kowloon, Hong Kong
| | - S C Wong
- Department of Health Technology and Informatics, Faculty of Health and Social Sciences, Hong Kong Polytechnic University, Kowloon, Hong Kong
| | - Parco M Siu
- School of Public Health, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, Hong Kong
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Pradhan G, Wu CS, Han Lee J, Kanikarla P, Guo S, Yechoor VK, Samson SL, Sun Y. Obestatin stimulates glucose-induced insulin secretion through ghrelin receptor GHS-R. Sci Rep 2017; 7:979. [PMID: 28428639 PMCID: PMC5430520 DOI: 10.1038/s41598-017-00888-0] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2016] [Accepted: 03/07/2017] [Indexed: 11/19/2022] Open
Abstract
Orexigenic hormone ghrelin and anorexic hormone obestatin are encoded by the same preproghrelin gene. While it is known that ghrelin inhibits glucose-stimulated insulin secretion (GSIS), the effect of obestatin on GSIS is unclear. Ghrelin's effect is mediated by its receptor Growth Hormone Secretagogue Receptor (GHS-R), but the physiologically relevant receptor of obestatin remains debatable. Here we have investigated the effect of obestatin on GSIS in vitro, in vivo and ex vivo, and tested whether obestatin regulates insulin secretion through GHS-R. We found that under hyperglycemic condition, obestatin augments GSIS in rat insulinoma cells (INS-1) and in pancreatic islets from ghrelin -/- mice. Surprisingly, obestatin-induced GSIS was absent in β-cells in which GHS-R was suppressed. Obestatin-induced insulin secretion was abolished in the circulation of Ghsr -/- mice, and in pancreatic islets isolated from Ghsr -/- mice. We also found that obestatin-induced GSIS was attenuated in islets isolated from β-cell-specific Ghsr knockout MIP-Cre/ERT;Ghsrf/f mice. Our data collectively demonstrate that obestatin is a potent insulin secretagogue under hyperglycemic condition, and obestatin's effect on insulin secretion is mediated by GHS-R in pancreatic β-cells. Our findings reveal an intriguing insight that obestatin and ghrelin have opposing effects on insulin secretion, and both are mediated through ghrelin receptor GHS-R.
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Affiliation(s)
- Geetali Pradhan
- USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA
- Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Chia-Shan Wu
- USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA
- Department of Nutrition and Food Science, Texas A&M University, College Station, TX, USA
| | - Jong Han Lee
- USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA
- College of Pharmacy, Gachon University, Incheon, 21936, Korea
| | - Preeti Kanikarla
- USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA
| | - Shaodong Guo
- Department of Nutrition and Food Science, Texas A&M University, College Station, TX, USA
| | - Vijay K Yechoor
- Department of Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Susan L Samson
- Department of Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Yuxiang Sun
- USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
- Department of Nutrition and Food Science, Texas A&M University, College Station, TX, USA.
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Colldén G, Tschöp MH, Müller TD. Therapeutic Potential of Targeting the Ghrelin Pathway. Int J Mol Sci 2017; 18:ijms18040798. [PMID: 28398233 PMCID: PMC5412382 DOI: 10.3390/ijms18040798] [Citation(s) in RCA: 101] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Revised: 04/03/2017] [Accepted: 04/06/2017] [Indexed: 02/07/2023] Open
Abstract
Ghrelin was discovered in 1999 as the endogenous ligand of the growth-hormone secretagogue receptor 1a (GHSR1a). Since then, ghrelin has been found to exert a plethora of physiological effects that go far beyond its initial characterization as a growth hormone (GH) secretagogue. Among the numerous well-established effects of ghrelin are the stimulation of appetite and lipid accumulation, the modulation of immunity and inflammation, the stimulation of gastric motility, the improvement of cardiac performance, the modulation of stress, anxiety, taste sensation and reward-seeking behavior, as well as the regulation of glucose metabolism and thermogenesis. Due to a variety of beneficial effects on systems’ metabolism, pharmacological targeting of the endogenous ghrelin system is widely considered a valuable approach to treat metabolic complications, such as chronic inflammation, gastroparesis or cancer-associated anorexia and cachexia. The aim of this review is to discuss and highlight the broad pharmacological potential of ghrelin pathway modulation for the treatment of anorexia, cachexia, sarcopenia, cardiopathy, neurodegenerative disorders, renal and pulmonary disease, gastrointestinal (GI) disorders, inflammatory disorders and metabolic syndrome.
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Affiliation(s)
- Gustav Colldén
- Institute for Diabetes and Obesity & Helmholtz Diabetes Center, Helmholtz Zentrum München German Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany.
| | - Matthias H Tschöp
- Institute for Diabetes and Obesity & Helmholtz Diabetes Center, Helmholtz Zentrum München German Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany.
- Division of Metabolic Diseases, Department of Medicine, Technische Universität München, 80333 Munich, Germany.
| | - Timo D Müller
- Institute for Diabetes and Obesity & Helmholtz Diabetes Center, Helmholtz Zentrum München German Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany.
- Institute for Diabetes and Obesity (IDO), Business Campus Garching-Hochbrück, Parkring 13, 85748 Garching, Germany.
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Labarthe A, Tolle V. [Ghrelin: a gastric hormone at the crossroad between growth and appetite regulation]. Biol Aujourdhui 2017; 210:237-257. [PMID: 28327282 DOI: 10.1051/jbio/2016027] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2016] [Indexed: 06/06/2023]
Abstract
Ghrelin is a 28 amino acid peptide hormone synthesized within the gastrointestinal tract. Initially identified as the endogenous ligand of the GHS-R1a (Growth Hormone Secretagogue Receptor 1a), ghrelin is a powerful stimulator of growth hormone (GH) secretion. At the crossroad between nutrition, growth and long-term energy metabolism, ghrelin also plays a unique role as the first identified gastric hormone increasing appetite and adiposity. However, the role of the ghrelin/GHS-R system in the physiology of growth, feeding behaviour and energy homeostasis needs to be better understood. Utilization of pharmacological tools and complementary animal models with deficiency in preproghrelin, ghrelin-O-acyl-transferase (GOAT - the enzyme that acylates ghrelin -) or GHS-R in situations of chronic undernutrition or high fat diet gives a more precise overview of the role of ghrelin in the pathophysiology of eating and metabolic disorders.
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Al Massadi O, López M, Tschöp M, Diéguez C, Nogueiras R. Current Understanding of the Hypothalamic Ghrelin Pathways Inducing Appetite and Adiposity. Trends Neurosci 2017; 40:167-180. [PMID: 28108113 DOI: 10.1016/j.tins.2016.12.003] [Citation(s) in RCA: 79] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2016] [Revised: 12/13/2016] [Accepted: 12/15/2016] [Indexed: 12/21/2022]
Abstract
Ghrelin is a multifaceted regulator of metabolism. Ghrelin regulates energy balance in the short term via induction of appetite and in the long term via increased body weight and adiposity. Recently, several central pathways modulating the metabolic actions of ghrelin were unmasked, and it was shown to act through different hypothalamic nuclei to induce feeding. Ghrelin also modulates glucose homeostasis, but the central mechanisms responsible for this action have not been studied in detail. Although ghrelin also acts through extrahypothalamic areas to promote feeding, this review specifically dissects hypothalamic control of ghrelin's orexigenic and adipogenic actions and presents current understanding of the intracellular ghrelin orexigenic pathways, including their dependence on other relevant systems implicated in energy balance.
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Affiliation(s)
- Omar Al Massadi
- Department of Physiology, School of Medicine-CiMUS, Instituto de Investigación Sanitaria (IDIS), University of Santiago de Compostela, Av de Barcelona s/n Santiago de Compostela (A Coruña), 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Spain.
| | - Miguel López
- Department of Physiology, School of Medicine-CiMUS, Instituto de Investigación Sanitaria (IDIS), University of Santiago de Compostela, Av de Barcelona s/n Santiago de Compostela (A Coruña), 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Spain
| | - Matthias Tschöp
- Helmholtz Diabetes Center, Helmholtz Zentrum München and German Center for Diabetes Research (DZD), Neuherberg, Germany; Division of Metabolic Diseases, Technische Universität München, Munich, Germany
| | - Carlos Diéguez
- Department of Physiology, School of Medicine-CiMUS, Instituto de Investigación Sanitaria (IDIS), University of Santiago de Compostela, Av de Barcelona s/n Santiago de Compostela (A Coruña), 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Spain
| | - Ruben Nogueiras
- Department of Physiology, School of Medicine-CiMUS, Instituto de Investigación Sanitaria (IDIS), University of Santiago de Compostela, Av de Barcelona s/n Santiago de Compostela (A Coruña), 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Spain.
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Aotani D, Ariyasu H, Shimazu-Kuwahara S, Shimizu Y, Nomura H, Murofushi Y, Kaneko K, Izumi R, Matsubara M, Kanda H, Noguchi M, Tanaka T, Kusakabe T, Miyazawa T, Nakao K. Development of ghrelin transgenic mice for elucidation of clinical implication of ghrelin. Endocr J 2017; 64:S31-S33. [PMID: 28652541 DOI: 10.1507/endocrj.64.s31] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
To elucidate the clinical implication of ghrelin, we have been trying to generate variable models of transgenic (Tg) mice overexpressing ghrelin. We generated Tg mice overexpressing des-acyl ghrelin in a wide variety of tissues under the control of β-actin promoter. While plasma des-acyl ghrelin level in the Tg mice was 44-fold greater than that of control mice, there was no differences in the plasma ghrelin level between des-acyl ghrelin Tg and the control mice. The des-acyl ghrelin Tg mice exhibited the lower body weight and the shorter body length due to modulation of GH-IGF-1 axis. We tried to generate Tg mice expressing a ghrelin analog, which possessed ghrelin-like activity (Trp3-ghrelin Tg mice). The plasma Trp3-ghrelin concentration in Trp3-ghrelin Tg mice was approximately 85-fold higher than plasma ghrelin (acylated ghrelin) concentration seen in the control mice. Because Trp3-ghrelin is approximately 24-fold less potent than ghrelin, the plasma Trp3-ghrelin concentration in Trp3-ghrelin Tg mice was calculated to have approximately 3.5-fold biological activity greater than that of ghrelin (acylated ghrelin) in the control mice. Trp3-ghrelin Tg mice did not show any phenotypes except for reduced insulin sensitivity in 1-year old. After the identification of ghrelin O-acyltransferase (GOAT), we generated doubly Tg mice overexpressing both mouse des-acyl ghrelin and mouse GOAT in the liver by cross-mating the two kinds of Tg mice. The plasma ghrelin concentration of doubly Tg mice was approximately 2-fold higher than that of the control mice. No apparent phenotypic changes in body weight and food intake were observed in doubly Tg mice. Further studies are ongoing in our laboratory to generate Tg mice with the increased plasma ghrelin level to a greater extent. The better understanding of physiological and pathophysiological significance of ghrelin from experiments using an excellent animal model may provide a new therapeutic approach for human diseases.
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Affiliation(s)
- Daisuke Aotani
- Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Hiroyuki Ariyasu
- The First Department of Medicine, Wakayama Medical University, Wakayama, Japan
| | - Satoko Shimazu-Kuwahara
- Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Yoshiyuki Shimizu
- Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Hidenari Nomura
- Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Yoshiteru Murofushi
- Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Kentaro Kaneko
- Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Ryota Izumi
- Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Masaki Matsubara
- Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Hajime Kanda
- Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Michio Noguchi
- Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Tomohiro Tanaka
- Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Toru Kusakabe
- Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Takashi Miyazawa
- Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Kazuwa Nakao
- Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan
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Allas S, Delale T, Ngo N, Julien M, Sahakian P, Ritter J, Abribat T, van der Lely AJ. Safety, tolerability, pharmacokinetics and pharmacodynamics of AZP-531, a first-in-class analogue of unacylated ghrelin, in healthy and overweight/obese subjects and subjects with type 2 diabetes. Diabetes Obes Metab 2016; 18:868-74. [PMID: 27063928 DOI: 10.1111/dom.12675] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2016] [Revised: 04/05/2016] [Accepted: 02/24/2016] [Indexed: 01/05/2023]
Abstract
AIM To explore the safety, pharmacokinetics and pharmacodynamics in humans of the unacylated ghrelin analogue AZP-531, designed to improve glycaemic control and reduce weight. METHODS Assessments, including glucose measurements, were performed in a three-part randomized study. In Part A, healthy subjects [n = 44, age 18-50 years, body mass index (BMI) 20-28 kg/m(2) ] received a single subcutaneous dose of 0.3, 3, 15, 30, 60 or 120 µg/kg AZP-531 or placebo. In Part B, overweight/obese subjects (n = 32, age 18-65 years, BMI 28-38 kg/m(2) ) and in Part C, patients with type 2 diabetes [T2D; n = 36, age 18-65 years, BMI 20-40 kg/m(2) , glycated haemoglobin (HbA1c) 7-10%] received AZP-531 or placebo for 14 days (daily doses of 3, 15, 30 or 60 µg/kg and 15, 2 × 30 or 60 µg/kg, respectively). RESULTS AZP-531 was well tolerated. Single- and multiple-dose pharmokinetic variables were similar. Maximum AZP-531 concentrations were typically reached at 1 h post-dose. Observed maximum concentration (Cmax ) and area under the curve were dose-proportional. The mean terminal half-life (t1/2 ) was 2-3 h. In Part B, AZP-531 doses of ≥15 µg/kg significantly improved glucose concentrations, without increasing insulin levels, suggesting an insulin-sensitizing effect. AZP-531 decreased mean body weight by 2.6 kg (vs 0.8 kg for placebo). In Part C, glucose variables improved in all groups, including placebo, suggesting a study effect in uncontrolled patients at baseline. Notwithstanding, AZP-531 60 µg/kg reduced HbA1c by 0.4% (vs 0.2% for placebo) and body weight by 2.1 kg (vs 1.3 kg for placebo). CONCLUSIONS AZP-531 was well tolerated in this first-in-human study. Its pharmacokinetic profile, suitable for once-daily dosing, and metabolic effects support further clinical development for T2D.
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Affiliation(s)
- S Allas
- Alizé Pharma, Ecully, France
| | | | - N Ngo
- Quintiles Early Clinical Development PK Department, Overland Park, KS, USA
| | | | | | - J Ritter
- Phase 1 Quintiles Unit, London, UK
| | | | - A J van der Lely
- Department of Medicine, Erasmus University Medical Centre, Rotterdam, The Netherlands
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Cowan E, Burch KJ, Green BD, Grieve DJ. Obestatin as a key regulator of metabolism and cardiovascular function with emerging therapeutic potential for diabetes. Br J Pharmacol 2016; 173:2165-81. [PMID: 27111465 DOI: 10.1111/bph.13502] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2016] [Revised: 04/05/2016] [Accepted: 04/15/2016] [Indexed: 01/01/2023] Open
Abstract
Obestatin is a 23-amino acid C-terminally amidated gastrointestinal peptide derived from preproghrelin and which forms an α helix. Although obestatin has a short biological half-life and is rapidly degraded, it is proposed to exert wide-ranging pathophysiological actions. Whilst the precise nature of many of its effects is unclear, accumulating evidence supports positive actions on both metabolism and cardiovascular function. For example, obestatin has been reported to inhibit food and water intake, body weight gain and gastrointestinal motility and also to mediate promotion of cell survival and prevention of apoptosis. Obestatin-induced increases in beta cell mass, enhanced adipogenesis and improved lipid metabolism have been noted along with up-regulation of genes associated with beta cell regeneration, insulin production and adipogenesis. Furthermore, human circulating obestatin levels generally demonstrate an inverse association with obesity and diabetes, whilst the peptide has been shown to confer protective metabolic effects in experimental diabetes, suggesting that it may hold therapeutic potential in this setting. Obestatin also appears to be involved in blood pressure regulation and to exert beneficial effects on endothelial function, with experimental studies indicating that it may also promote cardioprotective actions against, for example, ischaemia-reperfusion injury. This review will present a critical appraisal of the expanding obestatin research area and discuss the emerging therapeutic potential of this peptide for both metabolic and cardiovascular complications of diabetes.
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Affiliation(s)
- Elaine Cowan
- Queen's University Belfast, Institute for Global Food Security, School of Biological Sciences, Belfast, UK
| | - Kerry J Burch
- Queen's University Belfast, Wellcome-Wolfson Institute for Experimental Medicine, Belfast, UK
| | - Brian D Green
- Queen's University Belfast, Institute for Global Food Security, School of Biological Sciences, Belfast, UK
| | - David J Grieve
- Queen's University Belfast, Wellcome-Wolfson Institute for Experimental Medicine, Belfast, UK
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Inoue Y, Hayashi Y, Kangawa K, Suzuki Y, Murakami N, Nakahara K. Des-acyl ghrelin prevents heatstroke-like symptoms in rats exposed to high temperature and high humidity. Neurosci Lett 2016; 615:28-32. [PMID: 26773867 DOI: 10.1016/j.neulet.2016.01.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2015] [Revised: 12/24/2015] [Accepted: 01/05/2016] [Indexed: 10/22/2022]
Abstract
We have shown previously that des-acyl ghrelin decreases body temperature in rats through activation of the parasympathetic nervous system. Here we investigated whether des-acyl ghrelin ameliorates heatstroke in rats exposed to high temperature. Peripheral administration of des-acyl ghrelin significantly attenuated hyperthermia induced by exposure to high-temperature (35°C) together with high humidity (70-80%). Although biochemical analysis revealed that exposure to high temperature significantly increased hematocrit and the serum levels of aspartate amino transferase (AST), alanine transaminase (ALT), blood urea nitrogen (BUN), creatinine and electrolytes (Na(+), K(+), Cl(-)), most of these heatstroke-associated reactions were significantly reduced by treatment with des-acyl ghrelin. The level of des-acyl ghrelin in plasma was also found to be significantly increased under high-temperature conditions. These results suggest that des-acyl ghrelin could be useful for preventing heatstroke under high temperature condition.
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Affiliation(s)
- Yoshiyuki Inoue
- Department of Veterinary Physiology, Faculty of Agriculture, University of Miyazaki, Miyazaki 889-2192, Japan
| | - Yujiro Hayashi
- Asubio Pharma Co., Ltd., 6-4-3 Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan
| | - Kenji Kangawa
- Department of Biochemistry, National Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan
| | - Yoshihiro Suzuki
- Laboratory of Animal Health Science, School of Veterinary Medicine, Kitasato University, Aomori 034-8628, Japan
| | - Noboru Murakami
- Department of Veterinary Physiology, Faculty of Agriculture, University of Miyazaki, Miyazaki 889-2192, Japan
| | - Keiko Nakahara
- Department of Veterinary Physiology, Faculty of Agriculture, University of Miyazaki, Miyazaki 889-2192, Japan.
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Zhang C, Li L, Zhao B, Jiao A, Li X, Sun N, Zhang J. Ghrelin Protects against Dexamethasone-Induced INS-1 Cell Apoptosis via ERK and p38MAPK Signaling. Int J Endocrinol 2016; 2016:4513051. [PMID: 27190513 PMCID: PMC4844876 DOI: 10.1155/2016/4513051] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2015] [Revised: 03/10/2016] [Accepted: 03/23/2016] [Indexed: 11/17/2022] Open
Abstract
Glucocorticoid excess induces apoptosis of islet cells, which may result in diabetes. In this study, we investigated the protective effect of ghrelin on dexamethasone-induced INS-1 cell apoptosis. Our data showed that ghrelin (0.1 μM) inhibited dexamethasone-induced (0.1 μM) apoptosis of INS-1 cells and facilitated cell proliferation. Moreover, ghrelin upregulated Bcl-2 expression, downregulated Bax expression, and decreased caspase-3 activity. The protective effect of ghrelin against dexamethasone-induced INS-1 cell apoptosis was mediated via growth hormone secretagogue receptor 1a. Further studies revealed that ghrelin increased ERK activation and decreased p38MAPK expression after dexamethasone treatment. Ghrelin-mediated protection of dexamethasone-induced apoptosis of INS-1 cells was attenuated using the ERK inhibitor U0126 (10 μM), and cell viability increased using the p38MAPK inhibitor SB203580 (10 μM). In conclusion, ghrelin could protect against dexamethasone-induced INS-1 cell apoptosis, at least partially via GHS-R1a and the signaling pathway of ERK and p38MAPK.
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Affiliation(s)
- Chengshuo Zhang
- Hepatobiliary Surgery Department and Unit of Organ Transplantation, First Hospital of China Medical University, Shenyang 110001, China
| | - Le Li
- Hepatobiliary Surgery Department, Chifeng Municipal Hospital, Chifeng 024000, China
| | - Bochao Zhao
- Hepatobiliary Surgery Department and Unit of Organ Transplantation, First Hospital of China Medical University, Shenyang 110001, China
| | - Ao Jiao
- Hepatobiliary Surgery Department and Unit of Organ Transplantation, First Hospital of China Medical University, Shenyang 110001, China
| | - Xin Li
- Department of General Surgery, Fourth Hospital of China Medical University, Shenyang 110032, China
| | - Ning Sun
- Hepatobiliary Surgery Department and Unit of Organ Transplantation, First Hospital of China Medical University, Shenyang 110001, China
| | - Jialin Zhang
- Hepatobiliary Surgery Department and Unit of Organ Transplantation, First Hospital of China Medical University, Shenyang 110001, China
- *Jialin Zhang:
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Al Massadi O, López M, Fernø J, Diéguez C, Nogueiras R. What is the real relevance of endogenous ghrelin? Peptides 2015; 70:1-6. [PMID: 26003396 DOI: 10.1016/j.peptides.2015.04.027] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2015] [Revised: 04/06/2015] [Accepted: 04/07/2015] [Indexed: 12/11/2022]
Abstract
Ghrelin is a pleiotropic and ubiquitous gastric hormone implicated in body physiology. Ghrelin exhibits potent orexigenic actions and increases body weight and adiposity. Ghrelin is also involved in other metabolic functions among which we can highlight the GH releasing activity and the regulation of glucose homeostasis. Ghrelin needs the enzyme GOAT to be acylated, a step essential for binding to the GHSR1a receptor to exert its functions. Genetic animal models emerge as important tools to delineate the physiological relevance of ghrelin on energy balance. Despite the numerous reports using different genetically engineered mouse models targeting the ghrelin system, its endogenous relevance in metabolism seems to be less important than its pharmaceutical options.
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Affiliation(s)
- Omar Al Massadi
- Department of Physiology, School of Medicine-CIMUS, Instituto de Investigacion Sanitaria (IDIS), University of Santiago de Compostela, Avda. Barcelona s/n, 15782 Santiago de Compostela, Spain; CIBER Fisiopatologia de la Obesidad y Nutricion (CIBERobn), Santiago de Compostela (A Coruña) 15706, Spain.
| | - Miguel López
- Department of Physiology, School of Medicine-CIMUS, Instituto de Investigacion Sanitaria (IDIS), University of Santiago de Compostela, Avda. Barcelona s/n, 15782 Santiago de Compostela, Spain; CIBER Fisiopatologia de la Obesidad y Nutricion (CIBERobn), Santiago de Compostela (A Coruña) 15706, Spain
| | - Johan Fernø
- Department of Clinical Science, K. G. Jebsen Center for Diabetes Research, University of Bergen, Bergen N-5020, Norway
| | - Carlos Diéguez
- Department of Physiology, School of Medicine-CIMUS, Instituto de Investigacion Sanitaria (IDIS), University of Santiago de Compostela, Avda. Barcelona s/n, 15782 Santiago de Compostela, Spain; CIBER Fisiopatologia de la Obesidad y Nutricion (CIBERobn), Santiago de Compostela (A Coruña) 15706, Spain
| | - Rubén Nogueiras
- Department of Physiology, School of Medicine-CIMUS, Instituto de Investigacion Sanitaria (IDIS), University of Santiago de Compostela, Avda. Barcelona s/n, 15782 Santiago de Compostela, Spain; CIBER Fisiopatologia de la Obesidad y Nutricion (CIBERobn), Santiago de Compostela (A Coruña) 15706, Spain.
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Zhang SR, Fan XM. Ghrelin-ghrelin O-acyltransferase system in the pathogenesis of nonalcoholic fatty liver disease. World J Gastroenterol 2015; 21:3214-3222. [PMID: 25805927 PMCID: PMC4363750 DOI: 10.3748/wjg.v21.i11.3214] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2014] [Revised: 12/29/2014] [Accepted: 01/30/2015] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is currently considered as the most common liver disease in Western countries, and is rapidly becoming a serious threat to public health worldwide. However, the underlying mechanisms leading to the development of NAFLD are still not fully understood. The ghrelin-ghrelin O-acyltransferase (GOAT) system has recently been found to play a crucial role in both the development of steatosis and its progression to nonalcoholic steatohepatitis. Ghrelin, the natural ligand of the growth hormone secretagogue receptor, is a 28-amino acid peptide possessing a unique acylation on the serine in position 3 catalyzed by GOAT. The ghrelin-GOAT system is involved in insulin resistance, lipid metabolism dysfunction, and inflammation, all of which play important roles in the pathogenesis of NAFLD. A better understanding of ghrelin-GOAT system biology led to the identification of its potential roles in NAFLD. Molecular targets modulating ghrelin-GOAT levels and the biologic effects are being studied, which provide a new insight into the pathogenesis of NAFLD. This review probes into the possible relationship between the ghrelin-GOAT system and NAFLD, and considers the potential mechanisms by which the ghrelin-GOAT system brings about insulin resistance and other aspects concerning NAFLD.
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Müller TD, Nogueiras R, Andermann ML, Andrews ZB, Anker SD, Argente J, Batterham RL, Benoit SC, Bowers CY, Broglio F, Casanueva FF, D'Alessio D, Depoortere I, Geliebter A, Ghigo E, Cole PA, Cowley M, Cummings DE, Dagher A, Diano S, Dickson SL, Diéguez C, Granata R, Grill HJ, Grove K, Habegger KM, Heppner K, Heiman ML, Holsen L, Holst B, Inui A, Jansson JO, Kirchner H, Korbonits M, Laferrère B, LeRoux CW, Lopez M, Morin S, Nakazato M, Nass R, Perez-Tilve D, Pfluger PT, Schwartz TW, Seeley RJ, Sleeman M, Sun Y, Sussel L, Tong J, Thorner MO, van der Lely AJ, van der Ploeg LHT, Zigman JM, Kojima M, Kangawa K, Smith RG, Horvath T, Tschöp MH. Ghrelin. Mol Metab 2015; 4:437-60. [PMID: 26042199 PMCID: PMC4443295 DOI: 10.1016/j.molmet.2015.03.005] [Citation(s) in RCA: 771] [Impact Index Per Article: 77.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2015] [Revised: 03/11/2015] [Accepted: 03/11/2015] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND The gastrointestinal peptide hormone ghrelin was discovered in 1999 as the endogenous ligand of the growth hormone secretagogue receptor. Increasing evidence supports more complicated and nuanced roles for the hormone, which go beyond the regulation of systemic energy metabolism. SCOPE OF REVIEW In this review, we discuss the diverse biological functions of ghrelin, the regulation of its secretion, and address questions that still remain 15 years after its discovery. MAJOR CONCLUSIONS In recent years, ghrelin has been found to have a plethora of central and peripheral actions in distinct areas including learning and memory, gut motility and gastric acid secretion, sleep/wake rhythm, reward seeking behavior, taste sensation and glucose metabolism.
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Affiliation(s)
- T D Müller
- Institute for Diabetes and Obesity, Helmholtz Zentrum München, München, Germany
| | - R Nogueiras
- Department of Physiology, Centro de Investigación en Medicina Molecular y Enfermedades Crónicas, University of Santiago de Compostela (CIMUS)-Instituto de Investigación Sanitaria (IDIS)-CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain
| | - M L Andermann
- Division of Endocrinology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Z B Andrews
- Department of Physiology, Faculty of Medicine, Monash University, Melbourne, Victoria, Australia
| | - S D Anker
- Applied Cachexia Research, Department of Cardiology, Charité Universitätsmedizin Berlin, Germany
| | - J Argente
- Department of Pediatrics and Pediatric Endocrinology, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación La Princesa, Madrid, Spain ; Department of Pediatrics, Universidad Autónoma de Madrid and CIBER Fisiopatología de la obesidad y nutrición, Instituto de Salud Carlos III, Madrid, Spain
| | - R L Batterham
- Centre for Obesity Research, University College London, London, United Kingdom
| | - S C Benoit
- Metabolic Disease Institute, Division of Endocrinology, Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - C Y Bowers
- Tulane University Health Sciences Center, Endocrinology and Metabolism Section, Peptide Research Section, New Orleans, LA, USA
| | - F Broglio
- Division of Endocrinology, Diabetes and Metabolism, Dept. of Medical Sciences, University of Torino, Torino, Italy
| | - F F Casanueva
- Department of Medicine, Santiago de Compostela University, Complejo Hospitalario Universitario de Santiago (CHUS), CIBER de Fisiopatologia Obesidad y Nutricion (CB06/03), Instituto Salud Carlos III, Santiago de Compostela, Spain
| | - D D'Alessio
- Duke Molecular Physiology Institute, Duke University, Durham, NC, USA
| | - I Depoortere
- Translational Research Center for Gastrointestinal Disorders, University of Leuven, Leuven, Belgium
| | - A Geliebter
- New York Obesity Nutrition Research Center, Department of Medicine, St Luke's-Roosevelt Hospital Center, Columbia University College of Physicians and Surgeons, New York, NY, USA
| | - E Ghigo
- Department of Pharmacology & Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - P A Cole
- Monash Obesity & Diabetes Institute, Monash University, Clayton, Victoria, Australia
| | - M Cowley
- Department of Physiology, Faculty of Medicine, Monash University, Melbourne, Victoria, Australia ; Monash Obesity & Diabetes Institute, Monash University, Clayton, Victoria, Australia
| | - D E Cummings
- Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA
| | - A Dagher
- McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada
| | - S Diano
- Dept of Neurobiology, Yale University School of Medicine, New Haven, CT, USA
| | - S L Dickson
- Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
| | - C Diéguez
- Department of Physiology, School of Medicine, Instituto de Investigacion Sanitaria (IDIS), University of Santiago de Compostela, Spain
| | - R Granata
- Division of Endocrinology, Diabetes and Metabolism, Dept. of Medical Sciences, University of Torino, Torino, Italy
| | - H J Grill
- Department of Psychology, Institute of Diabetes, Obesity and Metabolism, University of Pennsylvania, Philadelphia, PA, USA
| | - K Grove
- Department of Diabetes, Obesity and Metabolism, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR, USA
| | - K M Habegger
- Comprehensive Diabetes Center, University of Alabama School of Medicine, Birmingham, AL, USA
| | - K Heppner
- Division of Diabetes, Obesity, and Metabolism, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006, USA
| | - M L Heiman
- NuMe Health, 1441 Canal Street, New Orleans, LA 70112, USA
| | - L Holsen
- Departments of Psychiatry and Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - B Holst
- Department of Neuroscience and Pharmacology, University of Copenhagen, Copenhagen N, Denmark
| | - A Inui
- Department of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - J O Jansson
- Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
| | - H Kirchner
- Medizinische Klinik I, Universitätsklinikum Schleswig-Holstein Campus Lübeck, Lübeck, Germany
| | - M Korbonits
- Centre for Endocrinology, William Harvey Research Institute, Barts and the London, Queen Mary University of London, London, UK
| | - B Laferrère
- New York Obesity Research Center, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA
| | - C W LeRoux
- Diabetes Complications Research Centre, Conway Institute, University College Dublin, Ireland
| | - M Lopez
- Department of Physiology, Centro de Investigación en Medicina Molecular y Enfermedades Crónicas, University of Santiago de Compostela (CIMUS)-Instituto de Investigación Sanitaria (IDIS)-CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain
| | - S Morin
- Institute for Diabetes and Obesity, Helmholtz Zentrum München, München, Germany
| | - M Nakazato
- Division of Neurology, Respirology, Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Kiyotake, Miyazaki, Japan
| | - R Nass
- Division of Endocrinology and Metabolism, University of Virginia, Charlottesville, VA, USA
| | - D Perez-Tilve
- Department of Internal Medicine, Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - P T Pfluger
- Institute for Diabetes and Obesity, Helmholtz Zentrum München, München, Germany
| | - T W Schwartz
- Department of Neuroscience and Pharmacology, Laboratory for Molecular Pharmacology, The Panum Institute, University of Copenhagen, Copenhagen, Denmark
| | - R J Seeley
- Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA
| | - M Sleeman
- Department of Physiology, Faculty of Medicine, Monash University, Melbourne, Victoria, Australia
| | - Y Sun
- Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA
| | - L Sussel
- Department of Genetics and Development, Columbia University, New York, NY, USA
| | - J Tong
- Duke Molecular Physiology Institute, Duke University, Durham, NC, USA
| | - M O Thorner
- Division of Endocrinology and Metabolism, University of Virginia, Charlottesville, VA, USA
| | - A J van der Lely
- Department of Medicine, Erasmus University MC, Rotterdam, The Netherlands
| | | | - J M Zigman
- Departments of Internal Medicine and Psychiatry, The University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - M Kojima
- Molecular Genetics, Institute of Life Science, Kurume University, Kurume, Japan
| | - K Kangawa
- National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan
| | - R G Smith
- The Scripps Research Institute, Florida Department of Metabolism & Aging, Jupiter, FL, USA
| | - T Horvath
- Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - M H Tschöp
- Institute for Diabetes and Obesity, Helmholtz Zentrum München, München, Germany ; Division of Metabolic Diseases, Department of Medicine, Technical University Munich, Munich, Germany
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Khatib MN, Gaidhane S, Gaidhane AM, Simkhada P, Zahiruddin QS. Ghrelin O Acyl Transferase (GOAT) as a Novel Metabolic Regulatory Enzyme. J Clin Diagn Res 2015; 9:LE01-5. [PMID: 25859472 PMCID: PMC4378754 DOI: 10.7860/jcdr/2015/9787.5514] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2014] [Accepted: 12/06/2014] [Indexed: 01/12/2023]
Abstract
BACKGROUND Obesity and Type 2 Diabetes Mellitus (T2DM) presents a growing threat to the global health. Evidences highlight an important role of ghrelin as a key regulator of glucose metabolism. The physiological functions of ghrelin are mediated by enzyme ghrelin-O-acyltransferase (GOAT) which is capable of generating the active form of this metabolic hormone. However, its exact mechanism of action and influence on energy balance and glucose metabolism is yet to be explored. OBJECTIVES To review the physiological role of GOAT in the regulation of energy balance and glucose metabolism and explore the potential therapeutic avenues of modulators of GOAT to counter the progression of obesity and T2DM. METHODS Publications were sought through electronic searches. The bibliographies of all papers, book, chapters and editorials were scanned and hand searches were also conducted for journals, and conference proceedings. CONCLUSION GOAT peptide modulates the insulin secretion as well as insulin sensitivity. Modulators of GOAT signaling like inhibitors of GOAT increases insulin secretion, enhance peripheral insulin sensitivity and thus counters obesity and T2DM. Modulators of GOAT can be a probable therapy for modifying food intake and for countering obesity and T2DM.
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Affiliation(s)
- Mahalaqua Nazli Khatib
- Professor, Department of Physiology, JN Medical College, Datta Meghe Institute of Medical Sciences, Wardha, Maharashtra, India
| | - Shilpa Gaidhane
- Associate Professor, Department of Medicine, JN Medical College, Datta Meghe Institute of Medical Sciences, Wardha, Maharashtra, India
| | - Abhay M. Gaidhane
- Professor, Department of Community Medicine, JN Medical College, Datta Meghe Institute of Medical Sciences, Wardha, Maharashtra, India
| | - Padam Simkhada
- Senior Lecturer in International Health ScHARR, University of Sheffield, UK and Centre for public Health Liverpool Johns Moores University, Liverpool, UK
| | - Quazi Syed Zahiruddin
- Professor, Department of Community Medicine, JN Medical College, Datta Meghe Institute of Medical Sciences, Wardha, Maharashtra, India
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Potential ghrelin-mediated benefits and risks of hydrogen water. Med Hypotheses 2015; 84:350-5. [PMID: 25649854 DOI: 10.1016/j.mehy.2015.01.018] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2014] [Accepted: 01/15/2015] [Indexed: 12/12/2022]
Abstract
Molecular hydrogen (H2) can scavenge hydroxyl radical and diminish the toxicity of peroxynitrite; hence, it has interesting potential for antioxidant protection. Recently, a number of studies have explored the utility of inhaled hydrogen gas, or of hydrogen-saturated water, administered parenterally or orally, in rodent models of pathology and in clinical trials, oftentimes with very positive outcomes. The efficacy of orally ingested hydrogen-rich water (HW) has been particularly surprising, given that only transient and rather small increments in plasma hydrogen can be achieved by this method. A recent study in mice has discovered that orally administered HW provokes increased gastric production of the orexic hormone ghrelin, and that this ghrelin mediates the favorable impact of HW on a mouse model of Parkinson's disease. The possibility that most of the benefits observed with HW in experimental studies are mediated by ghrelin merits consideration. Ghrelin is well known to function as an appetite stimulant and secretagogue for growth hormone, but it influences physiological function throughout the body via interaction with the widely express GHS-R1a receptor. Rodent and, to a more limited extent, clinical studies establish that ghrelin has versatile neuroprotective and cognitive enhancing activity, favorably impacts vascular health, exerts anti-inflammatory activity useful in autoimmune disorders, and is markedly hepatoprotective. The stimulatory impact of ghrelin on GH-IGF-I activity, while potentially beneficial in sarcopenia or cachectic disorders, does raise concerns regarding the long-term impact of ghrelin up-regulation on cancer risk. The impact of ingesting HW water on ghrelin production in humans needs to be evaluated; if HW does up-regulate ghrelin in humans, it may have versatile potential for prevention and control of a number of health disorders.
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Ghrelin: a link between ageing, metabolism and neurodegenerative disorders. Neurobiol Dis 2014; 72 Pt A:72-83. [PMID: 25173805 DOI: 10.1016/j.nbd.2014.08.026] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2014] [Revised: 06/28/2014] [Accepted: 08/20/2014] [Indexed: 12/13/2022] Open
Abstract
Along with the increase in life expectancy over the last century comes the increased risk for development of age-related disorders, including metabolic and neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington's diseases. These chronic disorders share two main characteristics: 1) neuronal loss in motor, sensory or cognitive systems, leading to cognitive and motor decline; and 2) a strong correlation between metabolic changes and neurodegeneration. In order to treat them, a better understanding of their complexity is required: it is necessary to interpret the neuronal damage in light of the metabolic changes, and to find the disrupted link between the peripheral organs governing energy metabolism and the CNS. This review is an attempt to present ghrelin as part of molecular regulatory interface between energy metabolism, neuroendocrine and neurodegenerative processes. Ghrelin takes part in lipid and glucose metabolism, in higher brain functions such as sleep-wake state, learning and memory consolidation; it influences mitochondrial respiration and shows neuroprotective effect. All these make ghrelin an attractive target for development of biomarkers or therapeutics for prevention or treatment of disorders, in which cell protection and recruitment of new neurons or synapses are needed.
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Wang Y, Shen Y, Zuo Q, Zhao L, Wan C, Tian P, Chen L, Wen F. Evaluation of ghrelin level and appetite regulation in patients with acute exacerbations of chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis 2014; 9:863-70. [PMID: 25152618 PMCID: PMC4140176 DOI: 10.2147/copd.s65195] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Background Appetite reduction is a major cause of cachexia in acute exacerbations of chronic obstructive pulmonary disease (AECOPD). This study tested the correlation of appetite and circulating levels of acylated ghrelin in patients with AECOPD. Methods Thirty-six patients with AECOPD and 23 healthy adults were enrolled in this study. Circulating total ghrelin, acylated ghrelin, and obestatin levels, Simplified Nutritional Appetite Questionnaire (SNAQ) score, and caloric intake were compared in patients and healthy controls. Additionally, the above parameters were compared between admission and discharge in the patients with AECOPD. Results Compared with healthy controls, SNAQ scores and caloric intake were significantly lower in patients with AECOPD, but there were no significant differences in total ghrelin, acyl ghrelin, or obestatin levels. In patients with AECOPD, the total ghrelin level was significantly higher at admission than on discharge, the SNAQ score and caloric intake were significantly increased at discharge when compared with admission, and there was no significant difference in acylated ghrelin level between admission and discharge. Conclusion We demonstrated lower appetite scores and caloric intake in patients with AECOPD, but could not confirm that these effects were caused by insufficient levels of the orexigenic peptide, acyl ghrelin. Further studies are needed to confirm our findings and to determine the mechanism regulating appetite in patients with AECOPD.
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Affiliation(s)
- Ye Wang
- Department of Respiratory Medicine, West China Hospital of Sichuan University and Division of Pulmonary Diseases, State Key Laboratory of Biotherapy of China, Chengdu, People's Republic of China
| | - Yongchun Shen
- Department of Respiratory Medicine, West China Hospital of Sichuan University and Division of Pulmonary Diseases, State Key Laboratory of Biotherapy of China, Chengdu, People's Republic of China
| | - Qiunan Zuo
- Department of Geriatrics, Sichuan Provincial People's Hospital, Chengdu, People's Republic of China
| | - Li Zhao
- Department of Respiratory Medicine, Guizhou People's Hospital, Guizhou, People's Republic of China
| | - Chun Wan
- Department of Respiratory Medicine, West China Hospital of Sichuan University and Division of Pulmonary Diseases, State Key Laboratory of Biotherapy of China, Chengdu, People's Republic of China
| | - Panwen Tian
- Department of Respiratory Medicine, West China Hospital of Sichuan University and Division of Pulmonary Diseases, State Key Laboratory of Biotherapy of China, Chengdu, People's Republic of China
| | - Lei Chen
- Department of Respiratory Medicine, West China Hospital of Sichuan University and Division of Pulmonary Diseases, State Key Laboratory of Biotherapy of China, Chengdu, People's Republic of China
| | - Fuqiang Wen
- Department of Respiratory Medicine, West China Hospital of Sichuan University and Division of Pulmonary Diseases, State Key Laboratory of Biotherapy of China, Chengdu, People's Republic of China
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Heppner KM, Tong J. Mechanisms in endocrinology: regulation of glucose metabolism by the ghrelin system: multiple players and multiple actions. Eur J Endocrinol 2014; 171:R21-32. [PMID: 24714083 DOI: 10.1530/eje-14-0183] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Ghrelin is a 28-amino acid peptide secreted mainly from the X/A-like cells of the stomach. Ghrelin is found in circulation in both des-acyl (dAG) and acyl forms (AG). Acylation is catalyzed by the enzyme ghrelin O-acyltransferase (GOAT). AG acts on the GH secretagogue receptor (GHSR) in the CNS to promote feeding and adiposity and also acts on GHSR in the pancreas to inhibit glucose-stimulated insulin secretion. These well-described actions of AG have made it a popular target for obesity and type 2 diabetes mellitus pharmacotherapies. However, despite the lack of a cognate receptor, dAG appears to have gluco-regulatory action, which adds an additional layer of complexity to ghrelin's regulation of glucose metabolism. This review discusses the current literature on the gluco-regulatory action of the ghrelin system (dAG, AG, GHSR, and GOAT) with specific emphasis aimed toward distinguishing AG vs dAG action.
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Affiliation(s)
- Kristy M Heppner
- Division of DiabetesObesity and Metabolism, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon, USA andDivision of EndocrinologyDiabetes and Metabolism, Department of Medicine, University of Cincinnati, 260 Stetson Street, Suite 4200, Cincinnati, Ohio 45219-0547, USA
| | - Jenny Tong
- Division of DiabetesObesity and Metabolism, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon, USA andDivision of EndocrinologyDiabetes and Metabolism, Department of Medicine, University of Cincinnati, 260 Stetson Street, Suite 4200, Cincinnati, Ohio 45219-0547, USA
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Tong J, Davis HW, Summer S, Benoit SC, Haque A, Bidlingmaier M, Tschöp MH, D'Alessio D. Acute administration of unacylated ghrelin has no effect on Basal or stimulated insulin secretion in healthy humans. Diabetes 2014; 63:2309-19. [PMID: 24550190 PMCID: PMC4066344 DOI: 10.2337/db13-1598] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Unacylated ghrelin (UAG) is the predominant ghrelin isoform in the circulation. Despite its inability to activate the classical ghrelin receptor, preclinical studies suggest that UAG may promote β-cell function. We hypothesized that UAG would oppose the effects of acylated ghrelin (AG) on insulin secretion and glucose tolerance. AG (1 µg/kg/h), UAG (4 µg/kg/h), combined AG+UAG, or saline were infused to 17 healthy subjects (9 men and 8 women) on four occasions in randomized order. Ghrelin was infused for 30 min to achieve steady-state levels and continued through a 3-h intravenous glucose tolerance test. The acute insulin response to glucose (AIRg), insulin sensitivity index (SI), disposition index (DI), and intravenous glucose tolerance (kg) were compared for each subject during the four infusions. AG infusion raised fasting glucose levels but had no effect on fasting plasma insulin. Compared with the saline control, AG and AG+UAG both decreased AIRg, but UAG alone had no effect. SI did not differ among the treatments. AG, but not UAG, reduced DI and kg and increased plasma growth hormone. UAG did not alter growth hormone, cortisol, glucagon, or free fatty acid levels. UAG selectively decreased glucose and fructose consumption compared with the other treatments. In contrast to previous reports, acute administration of UAG does not have independent effects on glucose tolerance or β-cell function and neither augments nor antagonizes the effects of AG.
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Affiliation(s)
- Jenny Tong
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Cincinnati, Cincinnati, OH
| | - Harold W Davis
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Cincinnati, Cincinnati, OH
| | - Suzanne Summer
- Clinical Translational Research Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
| | - Stephen C Benoit
- Department of Psychiatry, University of Cincinnati, Cincinnati, OH
| | - Ahrar Haque
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Cincinnati, Cincinnati, OH
| | - Martin Bidlingmaier
- Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität, Munich, Germany
| | - Matthias H Tschöp
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Cincinnati, Cincinnati, OHInstitute for Obesity and Diabetes, Helmholtz Center Munich and Division of Metabolic Diseases, Department of Medicine, Technical University, Munich, Germany
| | - David D'Alessio
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Cincinnati, Cincinnati, OHCincinnati Veterans Affairs Medical Center, Cincinnati, OH
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Mitrović O, Čokić V, Đikić D, Budeč M, Vignjević S, Subotički T, Diklić M, Ajtić R. Ghrelin receptors in human gastrointestinal tract during prenatal and early postnatal development. Peptides 2014; 57:1-11. [PMID: 24768902 DOI: 10.1016/j.peptides.2014.04.010] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2014] [Revised: 04/14/2014] [Accepted: 04/14/2014] [Indexed: 11/17/2022]
Abstract
The aim of our study was to investigate the appearance, density and distribution of ghrelin cells and GHS-R1a and GHS-R1b in the human stomach and duodenum during prenatal and early postnatal development. We examined chromogranin-A and ghrelin cells in duodenum, and GHS-R1a and GHS-R1b expression in stomach and duodenum by immunohistochemistry in embryos, fetuses, and infants. Chromogranin-A and ghrelin cells were identified in the duodenum at weeks 10 and 11 of gestation. Ghrelin cells were detected individually or clustered within the base of duodenal crypts and villi during the first trimester, while they were presented separately within the basal and apical parts of crypts and villi during the second and third trimesters. Ghrelin cells were the most numerous during the first (∼11%) and third (∼10%) trimesters of gestation development. GHS-R1a and GHS-R1b were detected at 11 and 16 weeks of gestation, showed the highest level of expression in Brunner's gland and in lower parts of duodenal crypts and villi during the second trimester in antrum, and during the third trimester in corpus and duodenum. Our findings demonstrated for the first time abundant duodenal expression of ghrelin cells and ghrelin receptors during human prenatal development indicating a role of ghrelin in the regulation of growth and differentiation of human gastrointestinal tract.
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Affiliation(s)
| | - Vladan Čokić
- Institute for Medical Research, University of Belgrade, Serbia
| | | | - Mirela Budeč
- Institute for Medical Research, University of Belgrade, Serbia
| | - Sanja Vignjević
- Institute for Medical Research, University of Belgrade, Serbia
| | | | - Miloš Diklić
- Institute for Medical Research, University of Belgrade, Serbia
| | - Rastko Ajtić
- Institute for Nature Conservation of Serbia, Belgrade, Serbia
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Özcan B, Neggers SJCMM, Miller AR, Yang HC, Lucaites V, Abribat T, Allas S, Huisman M, Visser JA, Themmen APN, Sijbrands EJG, Delhanty PJD, van der Lely AJ. Does des-acyl ghrelin improve glycemic control in obese diabetic subjects by decreasing acylated ghrelin levels? Eur J Endocrinol 2014; 170:799-807. [PMID: 23864339 DOI: 10.1530/eje-13-0347] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
OBJECTIVE The objective of this study was to assess the effects of a continuous overnight infusion of des-acyl ghrelin (DAG) on acylated ghrelin (AG) levels and glucose and insulin responses to a standard breakfast meal (SBM) in eight overweight patients with type 2 diabetes. Furthermore, in the same patients and two additional subjects, the effects of DAG infusion on AG concentrations and insulin sensitivity during a hyperinsulinemic-euglycemic clamp (HEC) were assessed. RESEARCH DESIGN AND METHODS A double-blind, placebo-controlled cross-over study design was implemented, using overnight continuous infusions of 3 and 10 μg DAG/kg per h and placebo to study the effects on a SBM. During a HEC, we studied the insulin sensitivity. RESULTS We observed that, compared with placebo, overnight DAG administration significantly decreased postprandial glucose levels, both during continuous glucose monitoring and at peak serum glucose levels. The degree of improvement in glycemia was correlated with baseline plasma AG concentrations. Concurrently, DAG infusion significantly decreased fasting and postprandial AG levels. During the HEC, 2.5 h of DAG infusion markedly decreased AG levels, and the M-index, a measure of insulin sensitivity, was significantly improved in the six subjects in whom we were able to attain steady-state euglycemia. DAG administration was not accompanied by many side effects when compared with placebo. CONCLUSIONS DAG administration improves glycemic control in obese subjects with type 2 diabetes through the suppression of AG levels. DAG is a good candidate for the development of compounds in the treatment of metabolic disorders or other conditions with a disturbed AG:DAG ratio, such as type 2 diabetes mellitus or Prader-Willi syndrome.
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Affiliation(s)
- Behiye Özcan
- Department of Internal MedicineErasmus University Medical Centre, PO Box 2040, 3000 CA, Rotterdam, The NetherlandsLilly Research LaboratoriesLilly Corporate Center, Indianapolis, Indiana 46285, USAAlizé Pharma69 130 Ecully, France
| | - Sebastian J C M M Neggers
- Department of Internal MedicineErasmus University Medical Centre, PO Box 2040, 3000 CA, Rotterdam, The NetherlandsLilly Research LaboratoriesLilly Corporate Center, Indianapolis, Indiana 46285, USAAlizé Pharma69 130 Ecully, France
| | - Anne Reifel Miller
- Department of Internal MedicineErasmus University Medical Centre, PO Box 2040, 3000 CA, Rotterdam, The NetherlandsLilly Research LaboratoriesLilly Corporate Center, Indianapolis, Indiana 46285, USAAlizé Pharma69 130 Ecully, France
| | - Hsiu-Chiung Yang
- Department of Internal MedicineErasmus University Medical Centre, PO Box 2040, 3000 CA, Rotterdam, The NetherlandsLilly Research LaboratoriesLilly Corporate Center, Indianapolis, Indiana 46285, USAAlizé Pharma69 130 Ecully, France
| | - Virginia Lucaites
- Department of Internal MedicineErasmus University Medical Centre, PO Box 2040, 3000 CA, Rotterdam, The NetherlandsLilly Research LaboratoriesLilly Corporate Center, Indianapolis, Indiana 46285, USAAlizé Pharma69 130 Ecully, France
| | - Thierry Abribat
- Department of Internal MedicineErasmus University Medical Centre, PO Box 2040, 3000 CA, Rotterdam, The NetherlandsLilly Research LaboratoriesLilly Corporate Center, Indianapolis, Indiana 46285, USAAlizé Pharma69 130 Ecully, France
| | - Soraya Allas
- Department of Internal MedicineErasmus University Medical Centre, PO Box 2040, 3000 CA, Rotterdam, The NetherlandsLilly Research LaboratoriesLilly Corporate Center, Indianapolis, Indiana 46285, USAAlizé Pharma69 130 Ecully, France
| | - Martin Huisman
- Department of Internal MedicineErasmus University Medical Centre, PO Box 2040, 3000 CA, Rotterdam, The NetherlandsLilly Research LaboratoriesLilly Corporate Center, Indianapolis, Indiana 46285, USAAlizé Pharma69 130 Ecully, France
| | - Jenny A Visser
- Department of Internal MedicineErasmus University Medical Centre, PO Box 2040, 3000 CA, Rotterdam, The NetherlandsLilly Research LaboratoriesLilly Corporate Center, Indianapolis, Indiana 46285, USAAlizé Pharma69 130 Ecully, France
| | - Axel P N Themmen
- Department of Internal MedicineErasmus University Medical Centre, PO Box 2040, 3000 CA, Rotterdam, The NetherlandsLilly Research LaboratoriesLilly Corporate Center, Indianapolis, Indiana 46285, USAAlizé Pharma69 130 Ecully, France
| | - Eric J G Sijbrands
- Department of Internal MedicineErasmus University Medical Centre, PO Box 2040, 3000 CA, Rotterdam, The NetherlandsLilly Research LaboratoriesLilly Corporate Center, Indianapolis, Indiana 46285, USAAlizé Pharma69 130 Ecully, France
| | - Patric J D Delhanty
- Department of Internal MedicineErasmus University Medical Centre, PO Box 2040, 3000 CA, Rotterdam, The NetherlandsLilly Research LaboratoriesLilly Corporate Center, Indianapolis, Indiana 46285, USAAlizé Pharma69 130 Ecully, France
| | - Aart Jan van der Lely
- Department of Internal MedicineErasmus University Medical Centre, PO Box 2040, 3000 CA, Rotterdam, The NetherlandsLilly Research LaboratoriesLilly Corporate Center, Indianapolis, Indiana 46285, USAAlizé Pharma69 130 Ecully, France
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Arellanes-Licea EDC, Báez-Ruiz A, Carranza ME, Arámburo C, Luna M, Díaz-Muñoz M. Daily patterns and adaptation of the ghrelin, growth hormone and insulin-like growth factor-1 system under daytime food synchronisation in rats. J Neuroendocrinol 2014; 26:282-95. [PMID: 24617825 DOI: 10.1111/jne.12145] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2013] [Revised: 02/07/2014] [Accepted: 03/06/2014] [Indexed: 11/29/2022]
Abstract
Daytime restricted feeding promotes the re-alignment of the food entrained oscillator (FEO). Endocrine cues which secretion is regulated by the transition of fasting and feeding cycles converge in the FEO. The present study aimed to investigate the ghrelin, growth hormone (GH) and insulin-like growth factor (IGF)-1 system because their release depends on rhythmic and nutritional factors, and the output from the system influences feeding and biochemical status. In a daily sampling approach, rats that were fed ad lib. were compared with rats on a reversed (daytime) and restricted feeding schedule by 3 weeks (dRF; food access for 2 h), also assessing the effect of acute fasting and refeeding. We undertook measurements of clock protein BMAL1 and performed somatometry of peripheral organs and determined the concentration of total, acylated and unacylated ghrelin, GH and IGF-1 in both serum and in its main synthesising organs. During dRF, BMAL1 expression was synchronised to mealtime in hypophysis and liver; rats exhibited acute hyperphagia, stomach distension with a slow emptying, a phase shift in liver mass towards the dark period and decrease in mass perigonadal white adipose tissue. Total ghrelin secretion during the 24-h period increased in the dRF group as a result of elevation of the unacylated form. By contrast, GH and IGF-1 serum concentration fell, with a modification of GH daily pattern after mealtime. In the dRF group, ghrelin content in the stomach and pituitary GH content decreased, whereas hepatic IGF-1 remained equal. The daily patterns and synthesis of these hormones had a rheostatic adaptation. The endocrine adaptive response elicited suggests that it may be associated with the regulation of metabolic, behavioural and physiological processes during the paradigm of daytime restricted feeding and associated FEO activity.
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Affiliation(s)
- E del C Arellanes-Licea
- Departamento de Neurobiología Celular y Molecular, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Querétaro, México
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Lee CY, Abizaid A. The gut-brain-axis as a target to treat stress-induced obesity. Front Endocrinol (Lausanne) 2014; 5:117. [PMID: 25101055 PMCID: PMC4102906 DOI: 10.3389/fendo.2014.00117] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2014] [Accepted: 07/03/2014] [Indexed: 12/16/2022] Open
Affiliation(s)
- Chooi Yeng Lee
- School of Pharmacy, Monash University Malaysia, Bandar Sunway, Malaysia
- *Correspondence:
| | - Alfonso Abizaid
- Department of Neuroscience, Carleton University, Ottawa, ON, Canada
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50
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Ghrelin inhibits ovarian epithelial carcinoma cell proliferation in vitro. Oncol Rep 2013; 30:2063-70. [PMID: 23982275 DOI: 10.3892/or.2013.2692] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2013] [Accepted: 06/18/2013] [Indexed: 11/05/2022] Open
Abstract
The only orexigenic peptide, ghrelin, which is primarily produced by the gastrointestinal tract, has been implicated in malignant cell proliferation and invasion. Ghrelin is a natural ligand of the growth hormone secretagogue receptor 1a (GHSR1a). However, the role of ghrelin in ovarian epithelial carcinoma remains unknown since the expression of GHSR1a in ovary is not confirmed. The aim of the present study was to assess expression of ghrelin and its receptor in human ovarian epithelial carcinoma and to examine the effect of ghrelin on carcinoma cell proliferation. Frozen sections of ovarian samples and the human ovarian epithelial carcinoma cell line, HO-8910, were used to characterize the expression of ghrelin/GHSR1a axis and the effect of ghrelin on proliferation. We found that ghrelin and GHSR1a are expressed in ovarian epithelial carcinoma in vivo and in vitro. Ghrelin inhibits the proliferation and growth of HO-8910 cells by G1 phase arrest, and this inhibition may be abolished by the ghrelin receptor antagonist D-Lys-3-GH-releasing peptide-6 and ghrelin neutralizing antibody. Ghrelin enhances HO-8910 cell apoptosis and autophagy. The activation of mammalian target of rapamycin (mTOR) signaling pathway blocks the effects of ghrelin-induced autophagy and apoptosis, therefore reverses the inhibition of HO-8910 cell proliferation induced by ghrelin. In conclusion, the present study demonstrates that ghrelin inhibits the proliferation of human HO-8910 ovarian epithelial carcinoma cells by inducing apoptosis and autophagy via the mTOR signaling pathway. This study provides a novel regulatory signaling pathway of ghrelin-regulated ovarian epithelial carcinoma growth and may contribute to ovarian cancer prevention and therapy.
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